Basic non-peptide bradykinin antagonists and pharmaceutical compositions therefrom

ABSTRACT

Non-peptide compounds of formula (I) having activity as specific antagonists of bradykinin (BK) B2 receptor. The compounds are chemically characterized by the presence of an alpha, alpha-disubstituted amino acid at least one amino group, free or salified, or the corresponding ammonium quaternary salt. These BK receptor antagonists are a novel class of medicaments which can be used in all the disorders in which said receptors are involved

FIELD OF THE INVENTION

The present invention relates to non-peptide, basic compounds and thederivatives thereof, having activity as specific antagonists ofbradykinin (BK) B2 receptor. The BK receptors antagonists are a novelclass of medicaments which can be used in all the conditions in whichsaid receptors are involved.

More particularly, the present invention relates to non-peptidecompounds which show high affinity and antagonistic activity towards B2receptor, having general formula (I):

in which

R₁ is a hydrogen atom or a C₁-C₄ alkyl group;

R₂ and R₃, which can be the same or different, are a C₁-C₄ alkyl group,or R₂ and R₃, together with the carbon atom which they are linked to,form a cyclic aliphatic group having 3 to 7 carbon atoms or aheterocyclic aliphatic group having 3 to 7 atoms, one or two of whichare selected from the group N, O, S and the others being C atoms;

R₄ and R₅, which can be the same or different, are a hydrogen atom or aC₁-C₄ alkyl group;

X is selected from the group consisting of halogen, OR₁, SR₁, CN, C₁-C₄alkyl;

B has at least one amino group with basic characteristics or atetraalkylammonium group and can be selected from the group consistingof:

NR₆(CH₂)nNHCOY, NR₆(CH₂)_(n)N(R₆)—Y, NR₆(CH₂)_(n)N(Y)₂, NR₆Y, N(Y)₂,N(Y)(CH₂)_(p)Y₁ and from the residues:

R₆ is a hydrogen atom, C₁-C₆ alkyl;

n=1-12;

Y is selected from: hydrogen, (CH₂)pY₁, (CH₂)_(p)NR₆Y₁, (CH₂)_(p)N(Y₁)₂,NR₅R₆, —NR₆(CH₂)_(q)Y₁ or from the following residues:

T is selected from the group of —NR₇R₈, —NR₁₄R₁₈R₁₉, —OR₆;

R₇ and R₈, which can be the same or different, are a hydrogen atom, aC₁-C₄ alkyl group, a cyclohexyl group, or NR₇R₈ together are a groupselected from:i) guanidine optionally substituted with 1 or 2 C₁-C₄alkyl or cyclohexyl groups, ii) a 5-7 membered nitrogen heterocycleoptionally containing another heteroatom selected from O, N, S;

Y₁ is selected from the group consisting of NR₇R₈, NR₁₄R₁₈R₁₉ or fromthe following residues:

Z is selected from the group consisting of H, C₁-C₆ alkyl, OR₆, SR₆,CF₃, OCOR₆, COR₁₀, NHCOR₆, SO₂R₆, SOR₆, CO₂R₆, N(R₆)₂, Cl, Br, NO₂, NH₂,CN, F, imidazole, phenyl, amidine, guanidine, guanidyl-methyl;

R₉ is selected from the group consisting of hydrogen, —(CH₂)_(q)-L,wherein L is selected from the group of —OH, —NR₅R₆, —NR₁₄R₁₈R₁₉,amidine optionally substituted with 1 or 2 C₁-C₄ alkyl groups, guanidineoptionally substituted with 1 or 2 C₁-C₄ alkyl groups;

R₁₀ is selected from the group consisting of OR₆, NR₆R₁₂;

R₁₁ is selected from the group consisting of hydrogen, —(CH₂)_(q)-L,—(CH₂)_(p)—NR₄—(CH₂)_(q)-L;

R₁₂ is a hydrogen atom, C₁-C₆ alkyl, COR₆,

R₁₃ is selected from the group consisting of H, C₁-C₆ alkyl,—(CH₂)_(p)W(CH₂)_(q)Y₁, Y, —COY, —CH₂—Y;

R₁₅ is selected from the group consisting of hydrogen or straight orbranched C₁-C₄ alkyl groups;

the —NR₁₆R₁₇ group is a 5-7 membered nitrogen aliphatic heterocycleoptionally containing another heteroatom selected from O, S, N;

the —NR₁₄R₁₈R₁₉ group is a quaternary ammonium group in which: R₁₄ isselected from the group consisting of straight or branched C₁-C₄ alkylgroups, R₁₈ and R₁₉, which can be the same or different, are a straightor branched C₁-C₄ alkyl group, or —NR₁₈R₁₉ is a 5-7 membered nitrogenheterocycle optionally containing another heteroatom selected from O, N,S;

W═CH₂, O, S, NR₄, N(R₄)₂;

p=1-6, q=1-6.

The present invention also embraces the corresponding pharmacologicallyacceptable salts with inorganic or organic acids selected from the groupof: hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, acetic,trifluoroacetic, propionic, oxalic, malic, maleic, succinic, malonic,aspartic, glutamic acids and possible geometrical isomers, opticalisomers, due to the presence of chiral centers, or mixtures thereof,including the racemates. The symbol

means that the configuration of the asymmetric carbon atoms can beeither S or R. Amines are known to be mainly in the protonated form atthe physiological pHs, i.e. they are in the form of quaternary ammonium,therefore this invention also comprises the analogues in which the aminonitrogen is in the form of tetraalkyl ammonium salt, i.e. the analoguesin which a quaternary nitrogen independent on pH is permanently present.

PRIOR ART

Bradykinin (BK) belongs to Kinins and forms, together with Kallidin andT-Kinin, the sub-group of Kinins present in mammals. Kinins play animportant role as mediators of pain and inflammation, both in thecentral and peripheral nervous system. They have peptide nature andbradykinin is, in particular, a nonapeptide(H-Arg¹-Pro²-Pro³-Gly⁴-Phe⁵-Ser⁶-Pro⁷-Phe⁸-Arg⁹-OH) produced by the bodyin physiopathological conditions.

Two types of Kinins receptors exist, B1 and B2. The main characteristicof the B1 receptor is that it is more inducible than constitutive. It isexpressed in tissues in inflammation or stress conditions. On the otherhand, B2 is a constitutive receptor normally present in all tissues andready to detect the action of the mediator during the inflammatoryprocesses. The cascade of the enzymatic processes which induces Kininsformation and degradation was described in detail in the review byBhoola et al.(Bhoola H. D., Figueroa C. D., Worthy K., Bioregulation ofKinins: Kallikreins, Kininogens and Kininases, Pharmacological Rev.1992; 44:4-80). Bradykinin and Kallidin are released from their proteinprecursors (known as kininogens), by proteolytic enzymes namedkininogenases. Among these, the main role is played by Kallikreins whichhowever, once released by the precursor, can exert their action only fora short time as they are quickly destroyed by a series of circulatingenzymes and membranes generically defined as Kininases. One of theseKininases cleaves bradykinin at the C-terminal arginine thus forming ades-Arg-BK which acts as B1 receptor agonist.

The activation of bradykinin B1 and B2 receptors induces relaxation ofvasal muscles with consequent hypotension, increase in vascularpermeability, contraction of smooth muscles of intestine and respiratorytract, stimulation of nociceptive neurons, alteration of ionicepithelial secretion, production of nitroxide and release of cytokinesby leukocytes and eicosanoids from different cell types. As aconsequence, antagonistic compounds of BK receptors can be considered anovel class of medicaments supposedly active in various disorders.Possible therapeutical applications for said antagonists areinflammatory, allergic and autoimmune disorders, such as asthma andchronic bronchitis (also induced by irritants), allergic, vasomotor andviral rhinitis, obstructive pulmonary disease (COPD), rheumatoidarthritis, chronic inflammatory diseases of the bowel (Crohn's diseaseand ulcerative colitis), glomerulonephritis, psoriasis, rash, acute andchronic cystitis; degenerative disorders characterized by fibrosis, suchas hepatic cirrhosis, glomerulopathies and pulmonary fibrosis,arteriosclerosis; thanks to their analgesic activity, in the treatmentof both acute and chronic pain, for example in burns, cephalea, insectsbites, chronic pain in cancer patients; in disorders of thecardiovascular apparatus such as septic, allergic and post-traumaticshocks, and hepatic cirrhosis by hepatorenal syndrome; as anticancer andantiangiogenetics; in the treatment of hypotension and of alopecia.

Different peptide and non-peptide antagonists of bradykinin B2 receptorare known in literature.

After the discovery of the first bradykinin B2 receptor antagonist,NPC-567, in 1985, a number of peptide antagonists have been synthesized,many of them, such as Icatibant (HOE-140) and Bradycor (Deltibant,CP-0127), being already in clinical phase.

The first non-peptide B2 antagonist of bradykinin was synthesized bySterling Winthrop in 1993, WIN 64338. Said compound, however, showed lowbinding activity to the human B2 receptor. Very interesting activity hasbeen showed by quinoline and imidazopyridine derivatives claimed byFujisawa, which starting from 1996, published pharmacological data andstudies concerning the novel non-peptide antagonist FR 173657 and theanalogues thereof. This compound was of paramount importance in thesearch for novel non-peptide B2 antagonists due to its selectivity,potency and activity after oral administration. After the publication ofFujisawa patents, similar structures were claimed in patents by Fournierand Hoechst. The compounds by Fournier also have a quinoline linked todichlorobenzene; a substituted sulfonamide connects this part of themolecule to an aromatic ring (optionally substituted with an amidine)through a basic linker (e.g.: propylenediamine, piperazine). Fournierannounced in May 1998 the start of the clinical phase I for thenon-peptide B2 antagonist LF 16.0687 (review: Altamura M. et al.,Regulatory Peptides, 1999, 80, 13-26).

In view of the possible advantages of the non-peptide antagonists(enzymatic and metabolic stabilities, high bioavailability) over peptideantagonists, the search for novel non-peptide B2 receptor antagonists isdesirable.

DETAILED DISCLOSURE

The present invention aims at providing novel non-peptide antagonists,having a reduced conformational freedom. The present invention disclosesnovel compounds of non-peptide nature, i.e. straight or cyclicsulfonamido derivatives of α,α-disubstituted amino acids, of generalformula (I), wherein R₁, R₂, R₃, R₄, R₅, X and B have the meaningsdefined above.

The presence of this particular category of amino acids causeslimitations in the molecular conformation, thus allowing modulation andoptimization of the interaction with the receptor through introductionof suitable pharmacophore groups.

These compounds are characterized both by high affinity and antagonisticactivity towards human B2 receptor and remarkable metabolic stability.

The compounds of the present invention are original over the compoundsclaimed in patent literature (WO 97/24349, WO 98/03503) in the light ofmutagenesis studies, which proved a different interaction with B2receptor, as well as conformational studies supported by molecularmodelling experiments and NMR analysis, which evidenced a defined,different conformation compared with that of analogues non containingα,α-disubstituted amino acids. In particular, a comparative studybetween the compounds of present invention and the analoguesnon-containing α,α-disubstituted amino acids, showed that differentvalues of the Φ and Ψ torsion angles are observed already starting fromthe intermediates.

The present invention also relates to the analogues in which an amine isin the form of a tetraalkyl ammonium compound, which is a similarcondition to that of amines at physiological pHs at which their activityis exerted.

In the definitions, C₁-C₄ allcyl group means a group selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl; C₁-C₆ alkylgroup means a group selected from methyl, ethyl, n-propyl, isopropyl,n-butyl, n-pentyl, n-hexyl; cyclic aliphatic group having 3 to 7 carbonatoms means a group selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl; aliphatic heterocyclic group having 3-7atoms means a group selected from pyrrolidine optionally substituted atthe N with a C₁-C₄ alkyl group, piperidine optionally substituted at theN with a C₁-C₄ alkyl group, tetrahydrofuran, tetrahydropyran,tetrahydrothiopyran; 5-7 membered aliphatic heterocyclic group means agroup selected from pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, azepine, diazepine, oxazepine.

More particularly, the present invention relates to the compounds ofgeneral formula (I) in which:

R₁ is a hydrogen atom or a C₁-C₄ alkyl group;

R₂ and R₃, which can be the same or different, are a C₁-C₄ alkyl group,or R₂ and R₃, together with the carbon atom which they are linked to,form a cyclic aliphatic group having 3 to 7 carbon atoms or aheterocyclic aliphatic group having 3 to 7 atoms one or two of which areselected from the group of N, O, S and the other being C atoms;

R₄ and R₅, which can be the same or different, are a hydrogen atom or aC₁-C₄ alkyl group;

X is selected from the group consisting of halogen, OR₁, SR₁, CN, C₁-C₄alkyl;

B has at least one amino group with basic characteristics or atetraalkylammonium and can be selected from the group consisting of:

R₆ is a hydrogen atom, C₁-C₆ alkyl;

Y is selected from: hydrogen, (CH₂)_(p)Y₁, (CH₂)_(p)NR₆Y₁,(CH₂)_(p)N(Y₁)₂, NR₅R₆, —NR₆(CH₂)_(p)Y₁ or from the following residues:

T is selected from the group of —NR₇R₈, —NR₁₄R₁₈R₁₉, —OR₆;

R₇ and R₈, which can be the same or different, are a hydrogen atom, aC₁-C₄ alkyl group, or NR₇R₈ is a group selected from: i) guanidineoptionally substituted with 1 or 2 C₁-C₄ alkyl groups, cyclohexyl, ii) a5-7 membered nitrogen heterocycle optionally containing anotherheteroatom selected from O, N, S;

Y₁ is selected from the group consisting of NR₇R₈, NR₁₄R₁₈R₁₉ or fromthe following residues:

Z is selected from the group consisting of H, C₁-C₆ alkyl, OR₆, SR₆,CF₃, OCOR₆, COR₁₀, NHCOR₆, SO₂R₆, SOR₆, CO₂R₆, N(R₆)₂, Cl, Br, NO₂, NH₂,CN, F, imidazole, phenyl, amidine, guanidine, guanidyl-methyl;

R₉ is selected from the group consisting of hydrogen, —(CH₂)q-L, whereinL is selected from the —OH group, —NR₅R₆, —NR₁₄R₁₈R₁₉, amidineoptionally substituted with 1 or 2 C₁-C₄ alkyl groups, guanidineoptionally substituted with 1 or 2 C₁-C₄ alkyl groups;

R₁₀ is selected from the group consisting of OR₆, NR₆R₁₂;

R₁₁ is selected from the group consisting of hydrogen, —(CH₂)_(q)-L,—(CH₂)_(p)—NR₄—(CH₂)_(q)-L;

R₁₂ is a hydrogen atom, C₁-C₆ alkyl, COR₆;

R₁₃ is selected from the group consisting of H, C₁-C₆ alkyl,—(CH₂)_(p)W(CH₂)_(q)Y₁, Y, —COY, —CH₂—Y;

R₁₄ is selected from the group consisting of straight or branched C₁-C₄alkyl groups;

R15 is selected from the group consisting of hydrogen or straight orbranched C₁-C₄ alkyl groups;

the —NR₁₆R₁₇ group is a 5-7 membered nitrogen aliphatic heterocycleoptionally containing another heteroatom selected from O, S, N;

the —NR₁₄R₁₈R₁₉ group is a quaternary ammonium group in which: R₁₄ isselected from the group consisting of straight or branched C₁-C₄ alkylgroups, R₁₈ and R₁₉, which can be the same or different, are a straightor branched C₁-C₄ alkyl group, or —NR₁₈R₁₉ is a 5-7 membered nitrogenheterocycle optionally containing another heteroatom selected from O, N,S;

W═CH₂, O, S, NR₄, N(R₄)₂;

p=1-6, q=1-6.

A class of preferred compounds are the compounds of general formula (I),in which:

B is selected from the group consisting of the residues:

Y is selected from: (CH₂)_(p)Y₁, (CH₂)_(p)NR₆Y₁, (CH₂)_(p)N(Y₁)₂, NR₅R₆,or from the following residues:

in which T is selected from the group of —NR₇R₈, —OR₆ and the othersubstituents are as defined above.

A particularly preferred class of compounds are the compounds in which:

R₁ is a hydrogen atom or methyl;

R₂ and R₃, which can be the same or different, are selected from methylor ethyl, or R₂ and R₃, together with the carbon atom which they arelinked to, form a cyclic aliphatic group having 3 to 7 carbon atoms;

R₄ and R₅, which can be the same or different, are a hydrogen or amethyl;

X is a chlorine atom;

B is a group selected from:

in which R₁₃ is H, or a Y═Y₁ group in which Y₁ is

R₁₁ is selected from the group consisting of hydrogen, —(CH₂)_(q)-L,—(CH₂)_(p)—NR₄—(CH₂)_(q)-L wherein L is selected from —OH, —NR₅R₆,amidine optionally substituted with 1 or 2 C₁-C₄ alkyl groups, guanidineoptionally substituted with 1 or 2 C₁-C₄ alkyl groups; and the othersubstituents are as defined above.

A further class of particularly preferred compounds of general formula(I) are those in which:

R₂ and R₃, which can be the same or different, are selected from methylor ethyl, or R₂ and R3, together with the carbon atom which they arelinked to, form a cyclic aliphatic group having 3 to 7 carbon atoms;

R₄ and R₅, which can be the same or different, are a hydrogen or amethyl;

X is a chlorine atom;

B contains at least two amino groups with basic characteristics, in thefree or salified form, and is selected from the group of:

in which R₁₃ is COY, CH₂Y, —(CH₂)_(p)W(CH₂)_(q)Y₁,

Y is a group (CH₂)pY₁, or is selected from:

wherein T is selected from —NR₇R₈, —OR₆;

R₇ and R₈, which can be can be the same or different, are a hydrogenatom, a C₁-C₄ alkyl group, or NR₇R₈ is a group selected from: i)guanidine optionally substituted with 1 or 2 C₁-C₄ alkyl groups,cyclohexyl, ii) a 5-7 membered nitrogen heterocycle optionallycontaining another heteroatom selected from O, N, S;

Y₁ is selected from the group consisting of —NR₇R₈ and from the residues

R₉ is selected from the group consisting of hydrogen, —(CH₂)_(q)-L,wherein L is selected from the group —NR₅R₆, amidine optionallysubstituted with 1 or 2 C₁-C₄ alkyl groups, guanidine optionallysubstituted with 1 or 2 C₁-C₄ alkyl groups; and the other substituentsare as defined above.

A second class of preferred compounds of general formula (I), containingat least one tetralkylammonium, are those in which:

R₁ is a hydrogen atom or methyl;

R₂ and R₃, which can be the same or different, are selected from methylor ethyl, or R₂ and R3, together with the carbon atom which they arelinked to, form a cyclic aliphatic group having 3 to 7 carbon atoms;

R₄ and R₅, which can be the same or different, are a hydrogen or amethyl;

X is a chlorine atom;

B is selected from the group consisting of NR₆Y, and from the residues:

Y is selected from: Y, COY, (CH₂)_(p)Y₁, NR₆(CH₂)_(q)Y₁ and from theresidues:

T is selected from the group —NR₇R₈, —NR₁₄R₁₈R₁₉, —OR₆;

Y₁ is selected from the group consisting of —NR₇R₈, —NR₇R₈R₁₄ or fromthe following residues:

and the other substituents are as defined above.

The compounds of general formula (I) can be prepared according to wellknown synthetic routes.

By way of example, and particularly interesting for the purposes of theinvention, the compounds of general formula (I) as defined above inwhich B is the group

can be prepared by condensation, in the presence of a suitablecondensing agent, of the intermediate of general formula (II)

with an acylating group, such as 2,6-diaminohexanoic acid, which iscommercially available. Compound (1) (intermediate of general formula(II) in which R₁═H) can be prepared according to the scheme reported inthe following.

Compound (1) is obtained through a series of reactions shown inScheme 1. The first step relates consists in the formation of thesulfonamido bond (4) obtained by condensation of intermediates (2) and(3). This reaction is carried out at room temperature, preferably inacetonitrile/water (2:1), in the presence of NaHCO₃. Said reaction takesplace with chlorine—bromine exchange on the benzyl position: theresulting products mixture is used as such as for the subsequent step.The halogen derivatives mixture is then reacted with a disubstitutedhydroxyquinoline (5), in the presence of potassium carbonate (K₂CO₃) andpotassium iodide (KI), in acetone under reflux, to obtain the etherderivative (6). The methyl ester of formula (6) in which R₁₄═CH₃, ishydrolysed in basic conditions to carboxylic acid (7), which is thencondensed with Boc-piperazine (8), to afford intermediate (9). Saidcondensation reaction is carried out according to a procedure known inthe peptide synthesis, using hydroxybenzotriazole to activate thecarboxylic component, a condensing agent such as1-ethyl-3-(3′-dimethylpropyl)carbodiimide and an amount of tertiaryamine, diisopropylethylamine, corresponding to three equivalentscompared with the condensing agent. Finally, compound (1) is obtained bycleaving the Boc group from intermediate (9), with a hydrochloric acidsolution (4N) in dioxane and isolating the free amine instead of thehydrochloride.

Compound of formula (2) is prepared as described in J. FluorineChemistry, 2000, 101:85-89.

Compound of formula (5), i.e. 2,4-dimethyl-8-hydroxyquinoline(R₄═R₅═CH₃), is prepared as disclosed in WO9640639.

In case R₁ is an alkyl group, in particular methyl, alkylation of thesulfonamido group of compound (6) is carried out; by way of example, thepreparation of intermediate (7) in which R₁=methyl, is shown in scheme2.

The sulfonamido nitrogen can be alkylated in dimethylformamide usingmethyl iodide as alkylating agent and potassium carbonate (K₂CO₃) asbase.

All compounds of general formula (I) can be obtained suitably changingthe procedure of scheme 2, by means of conventional acylation oralkylation reactions on the nitrogen atom in intermediates such ascompound (1) or the analogues thereof.

The intermediates and final products of the present invention arerecovered and purified through conventional procedures, such asextraction, crystallization, chromatography, precipitation and the like.

In case intermediates and final products have an asymmetric carbon atom,when the configuration (R,S) is not specified, the compounds are racemiccompounds or racemates.

In the present invention, the following abbreviations are used:DCM=dichloromethane; MeOH=methanol; THF=tetrahydrofuran;DMSO=dimethylsulfoxide; DMF=dimethylformamide; AcOEt=ethyl acetate;AcOH=acetic acid; TFA=trifluoroacetic acid; pTsOH=para-toluenesulfonicacid; PPA=poliphosphoric acid; NBS=N_(α)-bromosuccinimide, bpo=benzoylperoxide; Boc=tert-butoxycarbonyl; HOBt=1-hydroxy-benzotriazole;HOAt=1-hydroxy-7-aza-benzotriazole;EDC=1-ethyl-3-(3′-dimethylpropyl)carbodiimide;DIPEA=diisopropylethylamine; TLC=thin-layer chromatography; NMR=nuclearmagnetic resonance; FCC=Flash Column Chromatography; t_(R)=retentiontime.

The intermediates and final products of the present invention werecharacterized by analytic HPLC: column Symmetry 300, C18, 5 μm, 250×4.6mm, using A (0.1% TFA in H₂O) and B (0.1% TFA in acetonitrile) aseluents, with a gradient of 20 to 80% B in 20 minutes, λ=220 nm. For thecompounds characterized through nuclear magnetic resonance (NMR), thevalues of proton chemical shifts are reported, as well as the signalmultiplicity and the number of protons (in brackets).

The compounds of the invention are used in the treatment of all thosedisorders in which the activation of bradykinin receptor has to beblocked or reduced. They are particularly suitable for the treatment ofinflammatory, allergic and autoimmune disorders, such as asthma andchronic bronchitis, allergic, vasomotor and viral rhinitis, obstructivepulmonary disease (COPD), rheumatoid arthritis, chronic inflammatorydiseases of the bowel (Crohn's disease and ulcerative colitis),glomerulonephritis, psoriasis, rash, acute and chronic cystitis, hepaticcirrhosis, glomerulopathies and pulmonary fibrosis, arteriosclerosis,both acute and chronic pain, septic, allergic and post-traumatic shocks,hepatic cirrhosis by hepatorenal syndrome, hypotension, alopecia, or asanticancer and antiangiogenetics.

For use in therapy, the compounds of the invention will be suitablyformulated together with pharmaceutically acceptablecarriers/excipients. Preferred are pharmaceutical forms suitable for theoral administration, such as tablets, capsules, granules, powders,solutions, suspensions, syrups or the like. These pharmaceuticalpreparations can be prepared with conventional procedures usingingredients known in technique, such as ligands, disintegrants,lubricants, fillers, stabilizing agents, diluents, dyes, flavours,wetting agents and other excipients known to those skilled in the art.The oral formulations also comprise protracted-release forms, such asenteric-coated tablets or granules. The solid oral compositions can beprepared with conventional mixing, filling or compression methods. Theliquid oral preparations can be in the form of, for example, aqueous oroily suspensions or solutions, emulsions, syrups, or can be presented asdry product for reconstitution with water or other suitable carrierbefore use.

The dosage can range depending on the age and general conditions of thepatient, nature and severity of the disease or disorder and route andtype of administration. As a rule, in case of oral administration to ahuman adult patient, the compounds of the present invention will begenerally administered at a total ranging daily dosage from 1 to1000-mg, preferably from 5 to 300 mg, in a single dose or in subdivideddoses.

The following examples illustrate the invention in greater detail.

EXAMPLE 1 Intermediate of Formula (4) in Which R₂═CH₃, R₃═CH₂CH₃,R₁₄═CH₃ Methyl (R)-2-(2,4-dichloro-3-bromomethyl-benzenesulfonamido)-2-methyl methylbutanoate

A solution of (R)-methyl 2-(methylamino)-2-methylbutanoate (30 mg, 0.18mmol) in DMF (2ml) is added with 69 μl (0.40 mmol) of DIEA; then with125 mg (0.369 mmol) of 2,4-dichloro-3-bromomethyl-benzensulfonylchloride (2) at 0° C. The system is left to warm at room temperature;after reacting for approx. 30 minutes, the solution pH changes frombasic to strongly acid. The reaction is monitored by TLC: disappearanceof the spot of 2,4-dichloro-3-bromomethyl-benzensulfonyl chloride andformation of the final product are observed. DMF is evaporated off underreduced pressure and the reaction crude is purified on chromatographiccolumn (FCC) eluted with 100% chloroform, thereby obtaining 49 mg ofproduct as a colourless oil, in a 63% yield.

HPLC: t_(R)=21.84 min; MS: [M+NH₄]⁺=449.0; ¹H NMR (CDCl₃): 8.00 (d, 1H,J=9.0 Hz); 7.46 (d, 1H, J=9.0 Hz); 4.90 (s, 2H); 3.70 (s,3H); 2.01-1.88(m, 1H); 1.82-1.68 (m, 1H); 1.36 (s,3H); 0.74 (t, 3H, J=8.4 Hz).

EXAMPLE 2 Intermediate of Formula (6) in Which R₄═R₅═CH₃, R₂═CH₃,R₃═CH₂CH₃, R₁₄═CH₃ Methyl(R)-2-[2,4-dichloro-3-(2,4-dimethyl-8-quinolinoxymethyl)-benzene-sulfonamido]-2-methylbutanoate

A solution of the products obtained as described in example 1 (49 mg,0.283 mmol), in anhydrous acetone (10 ml) is added with 110 mg (0.283mmol) of 2,4-dimethyl-8-hydroxyquinoline, 58 mg of KI (0.349 mmol)previously dried over phosphoric anhydride at 75° C., and finally, 80 mg(0.579 mmol) of K₂CO₃. The solution is refluxed for about five hours anda half, until complete disappearance (monitored by HPLC) of the startingproducts. After cooling at room temperature, the is partitioned betweenAcOEt (50 ml) and a buffer solution at pH=4 (90 ml). The organic phaseis separated and washed with the buffer solution (50 ml); the aqueousphases are combined, and back-extracted with about 50 ml of AcOEt.Finally, the organic phase is washed with water and brine, dried oversodium sulfate, filtered and evaporated to dryness; the crude product ispurified by FCC eluting with hexane/AcOEt (2:1), to give 79 mg (yield:53%) of methyl(R)-2-[2,4-dichloro-3-(2,4-dimethyl-8-quinolinoxymethyl)benzenesulfonamido]-2-methylbutanoate,as a pale yellow oil.

HPLC: t_(R)=16.19 min; MS: [M+H]⁺=525.1; ¹H NMR CDCl₃): 8.02 (d, 1H,J=8.6 Hz); 7.60 (d, 1H, J=8.4 Hz); 7.47 (d, 1H, J=8.6 Hz); 7.36 (t, 1H,J=8.0 Hz); 7.21 (t, 1H, J=7.6 Hz); 7.11 (s, 1H); 6.00 (s, 1H); 5.66 (dd,2H, J₁=14.8 Hz, J₂=10.7 Hz); 2.64 (s,3H); 2.62 (s, 3H); 2.05-1.90 (m,1H, J=42.3 Hz); 1.83-1.71(m, 1H, J=28.7 Hz); 1.47 (s,3H); 0.78 (t, 3H,J=7.4 Hz).

The compounds of the examples reported in the following were preparedanalogously.

EXAMPLE 3 Intermediate of Formula (6) in Which R₄═R₅═CH₃, R₂═CH₃,R₃═CH₂CH₃, R₁₄═CH₃ Methyl(S)-2-[2,4-dichloro-3-(2,4-dimethyl-8-quinolinoxymethyl)-benzene-sulfonamido]-2-methylbutanoate.

HPLC: t_(R)=16.19 min; MS: [M+H]⁺=525.0; ¹H NMR (CDCl₃): 8.01 (d, 1H,J=8.6 Hz); 7.60 (d,1H, J=8.4 Hz); 7.47 (d, 1H, J=8.6 Hz); 7.37 (t, 1H,J=7.8 Hz); 7.12 (t, 1H, J=7.6 Hz); 6.00 (s, 1H); 5.65 (dd, 2H, J₁=14.8Hz, J₂=10.7 Hz); 3.69 (s, 3H); 2.65 (s,3H); 2.10-1.89 (m, 1H); 1.83-1.69(m, 1H); 1.37 (s,3H); 0.78 (t, 3H, J=7.4 Hz).

EXAMPLE 4 Intermediate of Formula (6) in Which R₄═R₅═CH₃, R₂═R₃═CH₃,R₁₄═C(CH₃)₃ tert-Butyl2-[2,4-dichloro-3-(2,4-dimethyl-8-quinolinoxymethyl)-benzene-sulfonamido]-2-methylpropanoate

HPLC: t_(R)=14.27 min; MS: [M+H]⁺=553.1; ¹H NMR (CDCl₃):8.05 (d, 1H,J=8.6 Hz); 7.61 (d, 1H, J=8.4 Hz); 7.47 (d, 1H, J=8.6 Hz); 7.38 (t, 1H,J=7.9 Hz); 7.21 (d, 1H, J=7.6 Hz); 7.13 (s, 1H); 6.09 (s, 1H); 5.67 (s,2H); 2.67 (s, 3H); 2.63 (s, 3H); 1.45 (s, 9H); 1.40 (s, 6H).

EXAMPLE 5 Intermediate of Formula (6) in Which R₄═H, R₅═CH₃, R₂═CH₃,R₃═CH₂CH₃, R₁₄═C(CH₃)₃ tert-Butyl2-[2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzene-sulfonamido]-2-methylpropanoate

MS: [M+H]⁺=539.0; ¹H NMR (CDCl₃): 8.08 (d, 1H, J=8.6 Hz); 8.03 (d, 1H,J=8.4 Hz); 7.51 (d,1H, J=8.6 Hz); 7.46 (d, 1H, J=7.1 Hz); 7.39 (t, 1H,J=7.6 Hz); 7.35-7.23 (m, 2H); 6.12 (s, 1H); 5.71 (s, 2H); 2.75 (s, 3H);1.48 (s, 9H); 1.43 (s, 6H).

EXAMPLE 6 Intermediate of Formula (6) in Which R₄═R₅═CH₃, R₂ and R₃,Together with the Carbon Atom Which They Are Linked To, Form aCyclopentyl, R₁₄═CH₃ Methyl1-[2,4-dichloro-3-(2,4-dimethyl-8-quinolinoxymethyl)]benzene-sulfonamido-1-cyclopentanecarboxylate

HPLC: t_(R)=11.16 min; MS: [M+H]⁺=537.0; ¹H NMR (DMSO): 8.64 (s, 1H),8.03 (d, 1H, J=8.6 Hz); 7.79-7.29 (m, 5H); 5.59 (s, 2H); 3.56 (s, 3H);2.89-2.57 (m, 6H); 1.98-1.85 (m, 4H); 1.60-1.48 (m, 2H); 1.48-1.38 (m,2H).

EXAMPLE 7 Intermediate of Formula (6) in Which R₄═H, R₅═CH₃, R₂ and R3,Together with the Carbon Atom Which They Are Linked To, Form aCyclopentyl, R₁₄═CH₃ Methyl1-[2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)]benzene-sulfonamido-1-cyclopentanecarboxylate

HPLC: t_(R)=15.43 min; MS: [M+H]⁺=523.2; ¹H NMR (CDCl₃): 8.07-8.01 (m,2H, J1=1.6 Hz, J2=8.6 Hz); 7.54 (d,1H, J=8.6 Hz); 7.49-7.38 (m, 2H);7.31 (d, 1H, J=8.4 Hz); 7.25 (dd, 1H, J₁=7.5 Hz; J₂=1.2 Hz); 5.70 (s,2H); 5.48 (s, 1H); 3.66 (s, 3H); 2.73 (s, 3H); 2.21-2.10 (m, 2H);2.01-1.91 (m, 2H); 1.75-1.65 (m, 4H).

EXAMPLE 8 Intermediate of Formula (6′) in Which R₁═CH₃, R₂ and R₃,Together with The Carbon Atom Which They Are Linked To, Form aCyclopentane Methyl1-[2,4-dichloro-3-(2,4-dimethyl-8-quinolinoxymethyl)]-1-N′-methyl-benzenesulfonamido-1-cyclopentanecarboxylate

A solution of methyl1-[2,4-dichloro-3-(2,4-dimethyl-8-quinolinoxymethyl)]benzenesulfonamido-1-cyclopentanecarboxylate(50 mg, 0.093 mmol) in 5 ml of DMF is added with CH₃I (19.2 ml, 0.306mmol) and 29 mg of K₂CO₃ (0.186 mmol), at 0° C. under nitrogenatmosphere. After stirring at room temperature for about 3 hours, thereaction mixture is poured in 50 ml of buffer solution pH=4.2, thenextracted with AcOEt (3×30 ml). The organic phase is subsequently washedwith water and brine, dried over sodium sulfate, filtered and evaporatedunder reduced pressure to obtain 52 mg (0.093 mmol) of desired productas a brown solid, in a quantitative yield.

HPLC: t_(R)=13.56 min; MS: [M+H]⁺=551.4; ¹H NMR (CDCl₃): 8.07 (d, 1H,J=8.6 Hz); 7.64 (d, 1H, J=8.6 Hz); 7.17 (s,1H); 5.69 (s, 2H); 3.78 (s,3H); 3.35 (s, 3H); 2.72 (d, 6H, J=44.9 Hz); 2.24 (m, 2H); 1.93 (m, 2H);1.63 (m, 4H).

EXAMPLE 9 Intermediate of Formula (7) in Which R₄═R₅═CH₃, R₂═CH₃,R₃═CH₂CH₃ Lithium(R)-2-[2,4-dichloro-3-(2,4-dimethyl-8-quinolinoxymethyl)-benzene-sulfonamido]-2-methylbutanoate

A solution of the product described in example 4 (79 mg, 0.15 mmol) inTHF/MeOH/H₂O (3:2:1, 6 ml) is added with 23 mg (0.96 mmol) of LiOH. Thereaction is stirred at room temperature for about 18 hours, thentemperature is raised to 45° C. for about 27 hours, to promote thehydrolysis reaction. THF and MeOH are then evaporated off under reducedpressure, and the alkaline solution is partitioned between AcOEt (25 ml)and water (25 ml). NaCl is added to break the resulting emulsion, thetwo phases are separated, the aqueous phase is acidified to pH=4 with 4NHCl, then extracted with AcOEt (25 ml). The organic phase is then washedwith brine, dried over sodium sulfate, filtered and dried to afford 64mg of product as a yellow solid, in an 82% yield.

HPLC t_(R)=14.36 min; MS: [M+H]⁺=511.0; ¹H NMR (DMSO): 8.09 (s, 1H);8.06 (d, 1H, J=8.6 Hz); 7.73 (d, 1H, J=8.6 Hz); 7.64 (d, 1H, J=8.3 Hz);7.46 (t, 1H, J=7.9 Hz); 7.34 (d, 1H, J=7.6 Hz); 7.27 (s, 1H), 5.51 (dd,2H, J1=13.8 Hz, J₂=10.8 Hz); 2.61 (s,3H); 2.54 (s, 3H); 1.62 (dd, 2H,J₁=14.4 Hz, J₂=7.1 Hz); 1.01 (s, 3H); 0.61 (t, 3H, J=7.1 Hz).

The compounds of the examples reported in the following were preparedanalogously.

EXAMPLE 10 Intermediate of Formula (7) in Which R₄═R₅═CH₃, R₂═CH₃,R₃═CH₂CH₃ Lithium(S)-2-[2,4-dichloro-3-(2,4-dimethyl-8-quinolinoxymethyl)-benzene-sulfonamido]-2-methylbutanoate

HPLC: t_(R)=14.24 min; ¹H NMR (CDCl₃): 8.09 (d, 1H, J=8.6 Hz); 7.62-7.47(m, 3H, J=48.5 Hz); 7.15 (s, 1H); 5.62 (d, 1H, J=9.6 Hz); 5.56 (s, 1H);5.47 (d, 1H, J=9.6 Hz); 2.66 (s, 3H); 2.53 (s, 3H); 1.86-1.64 (m, 2H,J=58.6 Hz); 1.37 (s, 3H); 0.95 (t, 3H, J=7.4 Hz).

EXAMPLE 11 Intermediate of Formula (7) in Which R₄═R₅═CH₃, R₂═R₃═CH₃2-[2,4-Dichloro-3-(2,4-dimethyl-8-quinolinoxymethyl)benzenesulfonamido]-2-methylpropionicacid

HPLC: t_(R)=9.09 min; MS: [M+H]⁺=497.0.

EXAMPLE 12 Intermediate of Formula (7) in Which R₄═H, R₅═CH₃, R₂═R₃═CH₃2-[2,4-Dichloro-3-(2-methyl-8-quinolinoxymethyl)benzenesulfonamido]-2-methylpropionicacid

HPLC: t_(R)=8.34 min; MS: [M+H]⁺=483.0, ¹H NMR (CDCl₃): 8.68 (d, 1H,J=8.6 Hz); 8.17 (d, 1H, J=8.7 Hz); 7.83 (t, 1H, J=8.1 Hz); 7.63 (d, 1H,J=8.7); 7.75-7.66 (m, 2H); 5.66 (s,2H); 5.50 (s, 1H); 2.94 (s, 3H); 1.52(s, 6H).

EXAMPLE 13 Intermediate of Formula (7) in Which R₄═R₅═CH₃, R₂ and R₃,Together with the Carbon Atom Which They Are Linked To, Form aCyclopentyl1-[2,4-Dichloro-3-(2,4-dimethyl-8-quinolinoxymethyl)]benzene-sulfonamido-1-cyclopentanecarboxylicacid

HPLC: t_(R)=9.969 min; MS: [M+H]⁺=523.0

EXAMPLE 14 Intermediate of Formula (7) in Which R₄═H, R₅═CH₃, R₂ and R3,Together with the Carbon Atom Which They Are Linked To, Form aCyclopentyl1-[2,4-Dichloro-3-(2-methyl-8-quinolinoxymethyl)]benzenesulfonamido-1-cyclopentanecarboxylicacid

HPLC: eq.: t_(R)=13.18 min(42.6%)-t_(R)=13.35 min(49.4%); MS:[M]⁻=507.0; ¹H NMR (DMSO): 12.57 (br s, 1H); 8.45 (s, 1H); 8.20 (d, 1H,J=8.4 Hz); 7.76 (d, 1H, J=8.6 Hz); 7.33-7.58 (m, 4H, J=77.1 Hz); 5.53(s, 2H); 2.59 (s, 3H); 1.94-1.84 (m, 4H, J=42.3 Hz); 1.60-1.30 (m, 4H,J=92.8 Hz).

EXAMPLE 15 Intermediate4-{1-[2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclopentanecarbonyl}-piperazine-1-carboxylicacid tert-butyl ester

A solution in DMF (2 ml) of the product described in example 15 (0.12mmol), is added with 22 mg (0.16 mmol) of HOAt and 29 mg (0.15 mmol) ofEDC.HCl. The mixture is stirred at 0° C. for about 30 min, then addedwith 32 mg (0.18 mmol) of tert-butyl-N-(piperazinyl)carbamate diluted in2 ml of DMF. The mixture is left to warm at room temperature understirring for 4 hours. The solvent is evaporated off and the product ispurified by preparative chromatography using a column Simmetry Prep™filled with RP-18 10 μm, eluting with a gradient of 90% water inacetonitrile to 50% water in acetonitrile during 40 minutes with a 10ml/min flow. The fractions corresponding to the desired product arecombined and the solvent is evaporated off thereby obtaining 48 mg ofthe product as a colourless oil in a 58% yield.

HPLC: t_(R)=16.68 min; MS: [M+H]⁺=691.5; ¹H NMR (DMSO-d₆) δ: 8.57 (1H,s), 8.02 (1H, d), 7.80 (1H, d), 7.66 (1H, d), 7.48 (1H, t), 7.35 (1H,d), 7.29 (1H, s), 5.54 (2H, s), 2.62 (3H, s), 2.55 (3H, s), 2.04-1.89(2H, m), 1.82-1.66 (4H, m), 1.41 (9H, s).

EXAMPLE 162,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-N-[1-(piperazine-1-carbonyl)-cyclopentyl]-benzenesulfonamide

A solution of 4N HCl in dioxane (2 ml) is dropwise added, at roomtemperature, to a methanol solution (4 ml) of the intermediate describedin Example 15 (0.072 mmol). The mixture is kept under stirring for aboutan hour, then evaporated to dryness under reduced pressure; the residueis taken up into a MeOH/toluene solution, which is then evaporated toyield a white solid. The product is then washed with ethyl ether,filtered, partitioned between AcOEt (25 ml) and a 5% NaHCO₃ aqueoussolution (25 ml); the two phases are separated and the organic phase iswashed with 25 ml of a 5% NaHCO₃ aqueous solution. The combined aqueousphases are back-extracted with 25 ml of AcOEt, finally the combinedorganic phases are washed with brine, dried over sodium sulfate,filtered and evaporated, thereby obtaining 25 mg a colourless oil in a66% yield.

HPLC: t_(R)=8.34 min; MS: [M+H]⁺=591.2; ¹H NMR (DMSO-d₆): 8.83 (brs,2H); 8.64 (s, 1H); 8.02 (d, 1H); 7.82 (d,1H); 7.6-7.4 (m, 4H);. 5.58 (s,2H); 3.4-2.6 (6H); 1.98 (m, 2H); 1.72 (m, 2H); 1.43 (s, 4H)

EXAMPLE 17 2,4-Dichloro-N-(1,1-dimethyl-2-oxo-2-piperazin-1-yl-ethyl)-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamide

HPLC: t_(R)=5.98 min; MS: [M+H]⁺=551.1; ¹H NMR (DMSO-d₆): 8.85 (brs,2H); 8.72 (s, 1H); 8.33 (brs, 1H); 8.07 (d,1H); 7.82 (d,1H); 7.63-7.40(m, 4H); 5.58 (s, 2H); 3.17 (m, 4H); 2.66 (s,3H); 1.23 (s, 6H)

EXAMPLE 18N-[2-[4-(2-(S)-Amino-6-dimethylaminohexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamide trifluoroacetate

A solution of 2,6-bis-tert-butyloxycarbonylamino-hexanoic acid (0.060mmol) and HOAt (11 mg, 0.081 mmol) in DMF (1 ml), cooled at 0° C., isadded with EDC.HCl (17 mg, 0.089 mmol) in a single portion. Afterstirring for 30 minutes, the compound described in example 17 (21 mg,0.037 mmol) dissolved in 2 ml of DMF is added at 0° C. and the mixtureis kept at this temperature for a further 30 minutes, then left to warmat room temperature.

After approx. 18 hours, stirring is discontinued and DMF is removedunder reduced pressure. The resulting residue is dissolved in 3 ml of a0.1% TFA aqueous solution and filtered through Anotop 25. The resultingaqueous solution is subjected to preparative chromatography eluting witha gradient of 90% water in acetonitrile to 50% water in acetonitrileduring 40 minutes, with a 10 ml/min flow. The fractions containing theproduct are recovered and combined and the solvent is evaporated off, toobtain 20 mg of product as a colourless oil. The oil is triturated inethyl ether (3 ml) and filtered under nitrogen. The resulting solid iswashed with ethyl ether and dried under nitrogen stream to afford 8.8 mgof white solid (yield 26%). The Boc groups are then removed as inExample 16.

¹H NMR (DMSO-d₆) δ: 9.38-9.26 (1H, brs), 8.72 (1H, s), 8.38-8.26 (1H,brs), 8.19-8.09 (3H, m), 8.07 (1H, d), 7.83 (1H, d), 7.64-7.39 (4H, m),5.58 (1H, s), 4.52-4.42 (1H, m), 3.04-2.95 (2H, m), 2.80-2.73 (6H, m),2.69-2.62 (5H, m), 1.77-1.54 (4H, m), 1.43-1.21 (8H, m).HPLC t_(R)=8.16min; MS: [M+H]⁺=707.2.

EXAMPLE 19N-{2-[4-(6-Guanidinohexyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)benzenesulfonamido-2-methyl-propionamidetris trifluoroacetate HPLC: t_(R)=6.46 min; MS: [M+H]⁺=692.2.

¹H NMR (DMSO-d6) δ: 9.38-9.26 (1H, brs), 8.72 (1H, s), 8.38-8.26 (1H,brs), 8.19-8.09 (3H, m), 8.07 (1H, d), 7.83 (1H, d), 7.64-7.39 (4H, m),5.58 (1H, s), 4.52-4.42 (1H, m), 3.04-2.95 (2H, m), 2.80-2.73 (6H, m),2.69-2.62 (5H, m), 1.77-1.54 (4H, m), 1.43-1.21 (8H, m).

EXAMPLE 204-{2-[2,4-Dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-2-methyl-propionyl}-piperazine-1-carboxamidine

HPLC: t_(R)=6.34 min; MS: [M+H]⁺=593.3; ¹H NMR (DMSO-d₆): 8.71 (s, 1H);8.06 (d, 1H); 7.82 (d,1H); 7.6-7.4 (m, 5H,); 5.57 (s, 2H); 3.6-3.5 (m,4H); 2.63 (s,3H); 1.23 (s, 6H)

EXAMPLE 21N-[2-[4-(2-(S)-Amino-5-guanidino-pentanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate

HPLC:t_(R)=7.62 min; MS: [M+H]⁺=707.1. ¹H NMR (DMSO-d₆) δ: 8.73 (1H, s),8.42-8.32 (1H, brs), 8.26-8.16 (3H, brs), 8.07 (1H, d), 7.82 (1H, d),7.66-7.00 (7H, m), 5.58 (1H, s), 3.19-3.09 (2H, m), 2.67(3H, s),1.80-1.45 (4H, m), 1.30-1.21 (6H, m).

EXAMPLE 22N-{2-[4-(6-Aminohexyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate

HPLC: t_(R)=6.02 min; MS: [M+H]⁺=649.9. ¹H NMR (DMSO-d₆) δ: 8.80 (1H,s), 8.08 (1H, d), 7.96-7.80 (3H, m), 7.83 (1H, d), 7.70-7.50 (3H, m),5.60 (1H, s), 4.58 (2H, m), 3.12-3.03 (2H, m), 3.02-2.84 (1H, m),2.81-2.69 (2H, m), 1.79 (2H, m), 1.60-1.50 (2H, m), 1.40-1.28 (4H, m),1.25 (6H, s).

EXAMPLE 23N-{2-[4-(Piperazin-2-yl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate

HPLC: t_(R)=7.54 min; MS: [M+H]⁺=663.0. ¹H NMR (DMSO-d₆) δ: 8.69 (1H,s), 8.53-8.31 (2H, m), 8.24-8.02 (1H, m), 8.07 (1H, d), 7.81 (1H, d),7.69-7.41 (4H, m), 5.59 (2H, s), 3.29-3.19 (2H, m), 2.96-2.81 (2H, m),2.68 (3H, m), 2.39-2.31 (2H, m), 2.06-1.93 (1H, m), 1.89-1.79 (2H, m),1.39-1.18 (9H, m).

EXAMPLE 24N-{2-[4-(Piperazin-1-ylacetyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidebis trifluoroacetate

HPLC: t_(R)=7.67 min; MS: [M+H]⁺=667.1. ¹H NMR (DMSO-d₆) δ: 9.00-8.78(1H, brs), 8.74 (1H, s), 8.44-8.21 (2H, brs), 8.07 (1H, d), 7.82 (1H,d), 7.67-7.40 (4H, m), 5.57 (1H, s), 3.66-3.45 (4H, m), 3.36-3.18 (3H,m), 3.12-2.98 (3H, m), 2.72-2.61 (3H, m), 1.70-1.60 (2H, m), 1.60-1.51(1H, m), 1.30-1.21 (7H, m).

EXAMPLE 25N-{2-[4-2-(Piperidin-4-yl-acetyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidebis trifluoroacetate

HPLC: t_(R)=8.32 min; MS: [M+H]⁺=676.1; ¹H NMR (DMSO-d₆) δ: 8.69 (1H,s), 8.53-8.31 (2H, m), 8.24-8.02 (1H, m), 8.07 (1H, d), 7.81 (1H, d),7.69-7.41 (4H, m), 5.59 (2H, s), 3.29-3.19 (2H, m), 2.96-2.81 (2H, m),2.68 (3H, m), 2.39-2.31 (2H, m), 2.06-1.93 (1H, m), 1.89-1.79 (2H, m),1.39-1.18 (9H, m).

EXAMPLE 26N-{2-[4-[N-(4-Piperidyl)glycyl]-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate

HPLC: t_(R)=7.42 min; MS: [M+H]⁺=691.2. ¹H NMR (DMSO-d₆) δ: 9.16-9.01(2H, m), 8.76-8.65 (2H, m), 8.43-8.22 (1H, m), 8.07 (1H, d), 7.82 (1H,d), 7.62-7.37 (4H, m), 5.56 (2H, s), 4.25-4.15 (2H, m), 3.01-2.88 (2H,m), 2.62 (3H, s), 2.27-2.18 (2H, m), 1.80-1.64 (2H, m), 1.25 (6H, s).

EXAMPLE 27N-{2-[4-(4-(2-Aminoethyl)piperazin-1-yl)acetyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetetra trifluoroacetate

HPLC t_(R)=7.59 min; MS: [M+H]⁺=720.2; ¹H NMR (DMSO-d₆) δ: 8.74 (1H, s),8.52-8.32 (1H, brs), 8.08 (1H, d), 7.83 (1H, d), 7.79-7.45 (6H, m), 5.58(2H, s), 3.69-3.55 (2H, m), 3.54-3.41 (2H, m), 3.00-2.90 (2H, m), 2.68(3H, s), 2.65-2.54 (2H, m), 1.25 (6H, s).

EXAMPLE 28N-{2-[4-(3-(R)-Amino-6-guanidino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate

HPLC: t_(R)=7.42 min; MS: [M+H]⁺=721.1; ¹H NMR (DMSO-d₆) δ: 8.71 (1H,s), 8.35-8.24 (1H, brs), 8.23-8.02 (3H, m), 8.07 (1H, d), 7.82 (1H, d),7.65-7.37 (5H, m), 5.57 (2H, s), 4.52-4.42 (1H, m), 3.13-3.04 (2H, m),2.64 (3H, s), 1.76-1.63 (2H, m), 1.56-1.17 (11H, m).

EXAMPLE 29N-{2-[4-(3-(S)-Amino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate

HPLC: t_(R)=7.64 min; MS: [M+H]⁺=707.1. ¹H NMR (DMSO-d₆) δ: 9.59-9.44(1H, brs), 8.70 (1H, s), 8.24 (1H, brd), 8.06 (1H, d), 7.89-7.76 (4H,m), 7.60-7.28 (5H, m), 5.56 (2H, s), 3.09-3.00 (2H, m), 2.88-2.73 (7H,m), 2.66-2.59 (3H, m), 1.78-1.52 (4H, m), 1.30-1.21 (6H, m).

EXAMPLE 30N-{2-[4-(3-(S)-Amino-7-dimethylamino-heptanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate

HPLC: t_(R)=7.59 min; MS: [M+H]⁺=721.2. ¹H NMR (DMSO-d₆) δ: 9.52-9.40(1H, brs), 8.70 (1H, s), 8.27 (1H, brd), 8.06 (1H, d), 7.84-7.71 (3H,m), 7.82 (1H, d), 7.61-7.28 (5H, m), 5.57 (2H, s), 3.04-2.96 (2H, m),2.80-2.75 (6H, m), 2.63 (3H, s), 1.65-1.53 (4H, m), 1.40-1.30 (2H, m),1.25 (6H, s).

EXAMPLE 31N-(3-Amino-propyl)-4-{2-[2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-2-methyl-propionyl}-piperazine-1-carboxamidinetris trifluoroacetate

HPLC: t_(R)=8.50 min; MS: [M+H]⁺=650.2; ¹H NMR (DMSO-d₆) δ: 8.70 (1H,s), 8.36-8.27 (1H, m), 8.06 (1H, d),7.85-7.71 (7H, m), 7.63-7.39 (4H,m), 5.58 (2H, s), 3.30-3.22 (2H, m), 2.90-2.79 (2H, m), 2.64 (3H, s),1.85-1.74 (2H, m), 1.24 (6H, s).

EXAMPLE 32N-[2-[4-(2-(S)-Amino-5-dimethylamino-pentanoyl))-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamide tris trifluoroacetate

HPLC: t_(R)=7.28 min; MS: [M+H]⁺=693.1. ¹H NMR (DMSO-d₆) d: 9.68-9.40(1H, m), 8.76 (1H, s), 8.33-8.16 (4H, m), 8.06 (1H, d), 7.83 (1H, d),7.62-7.35 (4H, m), 5.56 (2H, s), 4.60-4.45 (1H, m), 3.12-3.01 (2H, m),2.79-2.73 (6H, m), 2.62 (3H, s), 1.78-1.59 (4H, m), 1.32-1.19 (6H, m).

EXAMPLE 33(S)—N-{2-[1′-(2-Amino-5-guanidino-pentanoyl)-[4,4′]bipiperidinyl-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamide

HPLC: t_(R)=7.96 min; MS: [M+H]⁺=789.5; ¹H NMR (DMSO-d₆): 8.57 (s, 1H);8.22 (d, 1H); 8.06 (bs, 2H); 8.05-8.04 (d,1H); 7.80 (d, 1H); 7.56-7.36(5H); 5.55 (s, 2H); 3.92-3.84 (m, 1H); 3.11-3.01 (m, 4H); 2.60 (s,3H);1.80-0.99 (22H)

EXAMPLE 342,4-Dichloro-N-(2-{4-[2-(3,5-dimethyl-piperazin-1-yl)-ethyl]-3,5-dimethyl-piperazin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-3-(2-methyl-4a,8a-dihydro-quinolin-8-yloxymethyl)-benzenesulfonamide

HPLC: t_(R)=5.87 min; MS: [M+H]⁺=719.2; ¹H NMR (DMSO-d₆): 8.90 (d, 1H);8.76 (s, 1H); 8.27-8.18 (m, 2H); 8.05 (d,1H); 7.85 (d, 1H); 7.56-7.36(3H); 5.57 (s, 2H); 2.62 (s, 3H); 2.00-2.04 (t, 2H); 1.34-1.16 (18H)

EXAMPLE 35N-(2-{4-[4-(2-(S)Amino-5-guanidino-pentanoyl)-piperazin-1-yl]-piperidin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamide

HPLC:t_(R)=6.65 min; MS: [M+H]⁺=790.4; ¹H NMR (DMSO-d₆): 8.57 (s, 1H);8.22 (d, 1H); 8.06 (bs, 2H); 8.05 (d,1H); 7.80 (d, 1H); 7.56-7.36 (5H);5.60 (s, 2H); 4.53-4.37 (4H); 2.62 (s,3H); 1.82-1.45 (8H); 1.28-1.12(9H)

EXAMPLE 362,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfinicacid [1-(4-piperazin-1-yl-piperidine-1-carbonyl)-cyclopentyl]-amide

HPLC: t_(R)=5.70 min; MS: [M+H]⁺=674.3; ¹H NMR (DMSO-d₆): 8.57 (s, 1H);8.22 (d, 1H); 8.06 (bs, 2H); 8.04 (d,1H); 7.80 (d, 1H); 7.56-7.36 (5H);5.60 (s, 2H); 4.53-4.37 (4H); 2.62 (s,3H); 1.82-1.45 (8H); 1.28-1.12(9H)

EXAMPLE 372,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfinicacid(1-{4-[4-(2-S-amino-6-guanidino-hexanoyl)-piperazin-1-yl]-piperidine-1-carbonyl}-cyclopentyl)-amide

HPLC: t_(R)=7.29 min; MS: [M+H]⁺=844.4; ¹H NMR (DMSO-d₆): 8.57 (s, 1H);8.3-8.1 (bs, 3H); 8.02 (d, 1H); 7.82 (d, 1H); 5.58 (s, 2H); 4.65-4.48(m, 4H); 3.08 (m, 1H); 2.69 (s,3H); 2.61 (m, 3H)

EXAMPLE 382,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfinicacid(1-{4-[4-(2-S-amino-5-guanidino-pentanoyl)-piperazin-1-yl]-piperidine-1-carbonyl}-cyclopentyl)-amide

HPLC: t_(R)=7.26 min; MS: [M+H]⁺=830.4; ¹H NMR (DMSO-d₆): 8.58 (s, 1H);8.17 (bs, 3H); 8.02 (d, 1H); 7.82 (d,1H); 5.58 (s, 2H); 4.65-4.28 (m,5H); 3.11 (m, 1H); 2.69 (s,3H); 2.61 (m, 3H)

EXAMPLE 392,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfinicacid [1-(4-piperidin-4-yl-piperazine-1-carbonyl)-cyclopentyl]-amide

HPLC: t_(R)=7.59 min; MS: [M+H]⁺=674.3; ¹H NMR (DMSO-d₆): 8.8-8.3 (bs,3H); 8.02 (d, 1H); 7.82 (d, 1H); 7.80-7.25 (5H); 5.57 (s, 2H); 4.52 (bs,2H); 2.92 (m, 4H); 2.66 (s,3H); 2.59 (s, 3H); 2.30-1.60 (9H); 1.44 (m,4H)

EXAMPLE 402,4-Dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfinic acid{2-[4-(2-guanidino-ethyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-amide

HPLC: t_(R)=5.68 min; MS: [M+H]⁺=636.3; ¹H NMR (DMSO-d₆): 8.69 (s, 1H);8.32 (bs, 1H); 8.06 (d, 1H); 7.82 (d,1H); 7.6-7.4 (7H); 5.57 (s, 2H);3.6-3.5 (m, 4H); 2.65 (s,3H)

EXAMPLE 412,4-Dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfinic acid(2-{4-[2-S-amino-5-(N′,N″-diethyl-guanidino)-pentanoyl]-piperazin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-amide

HPLC: t_(R)=7.31 min; MS: [M+H]⁺=763.4; ¹H NMR (DMSO-d₆): 8.71 (s, 1H);8.22 (m, 3H); 8.05 (d, 1H); 7.82 (d,1H); 7.57 (d, 1H); 7.52-7.34 (5H);5.55 (s, 2H); 4.50 (s, 1H); 3.19 (m, 4H); 2.62 (s,3H); 1.69 (m, 2H);1.54 (m, 2H); 1.25 (s, 3H); 1.23 (s, 3H);. 1.10 (t, 6H)

EXAMPLE 422,4-Dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfinic acid(2-{4-[2-R-amino-5-(N′,N″-diethyl-guanidino)-pentanoyl]-piperazin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-amide

HPLC: t_(R)=7.31 min; MS: [M+H]⁺=763.3; ¹H NMR (DMSO-d₆): 8.71 (s, 1H);8.22 (m, 3H); 8.05 (d, 1H); 7.82 (d,1H); 7.57 (d, 1H); 7.52-7.34 (5H);5.55 (s, 2H); 4.50 (s, 1H); 3.19 (m, 4H); 2.62 (s,3H); 1.69 (m, 2H);1.54 (m, 2H); 1.25 (s, 3H); 1.23 (s, 3H); 1.10 (t, 6H)

EXAMPLE 43(2S)—N-(1-{4-[2-Amino-6-(N′,N″-diethyl-guanidino)-hexanoyl]-piperazine-1-carbonyl}-cyclopentyl)-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide

HPLC: t_(R)=8.47 min; MS: [M+H]⁺=817.2; ¹H NMR (DMSO-d₆): 8.62 (s, 1H);8.14 (s, 3H); 8.02 (d, 1H); 7.74-7.22 (6H); 5.57 (s, 2H); 4.47 (m, 1H);3.18 (m, 4H); 3.12 (m, 3H); 2.65 (s,3H); 2.58 (s, 3H); 1.97 (m, 2H);1.79-1.65 (4H); 1.56-1.25 (8H); 1.10 (t, 6H)

EXAMPLE 44N-(1-{4-[2-(S)Amino-6-(N′,N″-diethyl-guanidino)-pentanoyl]-piperazine-1-carbonyl}-cyclopentyl)-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide

HPLC:t_(R)=8.97 min; MS: [M+H]+=803.2; ¹H NMR (DMSO-d₆): 8.62 (s, 1H);8.14 (s, 3H); 8.02 (d, 1H); 7.74-7.22 (6H); 5.57 (s, 2H); 4.47 (m, 1H);3.18 (m, 4H); 3.12 (m, 3H); 2.65 (s,3H); 2.58 (s, 3H); 1.97 (m, 2H);1.79-1.65 (4H); 1.56-1.25 (8H); 1.10 (t, 6H)

EXAMPLE 45N-[2-[4-(2-(S)-Amino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide

¹H NMR (DMSO-d₆) δ: 9.58-9.44 (1H, brs), 8.73 (1H, s), 8.27-8.11 (3H,m), 8.07 (1H, d), 7.88-7.36 (5H, m), 5.60 (2H, s), 4.56-4.42 (1H, m),3.07-2.94 (2H, m), 2.81-2.61 (12H, m), 1.79-1.54 (4H, m), 1.46-1.16(10H, m). HPLC: t_(R)=13.34 min.MS: [M+H]⁺ 721

EXAMPLE 46N-[2-[4-(3-(S)-Amino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide

¹H NMR (DMSO-d₆) δ: 9.54-9.41 (1H, brs), 8.69 (1H, s), 8.06 (1H, d),7.88-7.28 (7H, m), 5.57 (2H, s), 3.08-2.99 (2H, m), 2.88-2.73 (7H, m),2.72-2.57 (6H, m), 1.76-1.53 (4H, m), 1.30-1.20 (7H, m). HPLC:t_(R)=13.56 min.MS: [M+H]⁺ 721

EXAMPLE 47N-[2-[4-(3-(S)-Amino-6-dimethylamino-heptanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide

¹H NMR (DMSO-d₆) δ: 9.51-9.37 (1H, brs), 8.69 (1H, s), 8.06 (1H, d),7.87-7.29 (7H, m), 5.57 (2H, s), 3.05-2.95 (2H, m), 2.86-2.73 (7H, m),2.73-2.55 (6H, m), 1.67-1.52 (4H, m), 1.43-1.29 (2H, m), 1.24 (6H, s).HPLC: t_(R)=13.56 min. MS: [M+H]⁺ 735

EXAMPLE 48N-[2-[4-(2-(S)-Amino-5-guanidino-pentanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide

¹H NMR (DMSO-d₆) δ: 8.72 (1H, s), 8.24-8.12 (3H, m), 8.07 (1H, d),7.86-6.92 (9H, m), 5.60 (2H, s), 4.54-4.44 (1H, m), 3.19-3.07 (2H, m),2.79-2.61 (6H, m), 1.77-1.46 (4H, m), 1.29-1.20 (6H, m). HPLC:t_(R)=8.32 min. MS: [M+H]⁺ 721

EXAMPLE 49N-[2-[4-(2-(S)-Amino-6-guanidino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide

¹H NMR (DMSO-d₆) δ: 8.71 (1H, s), 8.24-8.00 (4H, m), 7.88-6.74 (9H, m),5.59 (2H, s), 4.54-4.40 (1H, m), 3.13-3.03 (2H, m), 2.76-2.59 (6H, m),1.77-1.62 (2H, m), 1.54-1.43 (2H, m), 1.28-1.22 (6H, m). HPLC:t_(R)=8.38 min. MS: [M+H]⁺ 735

EXAMPLE 50N-[2-[4-(2-(S)-Amino-5-dimethylamino-pentanoyl))-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide

¹H NMR (DMSO-d₆) d: 9.53-9.40 (1H, brs), 8.72 (1H, s), 8.29-8.13 (3H,m), 8.06 (1H, d), 7.86-7.31 (4H, m), 5.58 (2H, s), 4.57-4.46 (1H, m),3.12-3.01 (2H, m), 2.80-2.73 (6H, m), 2.73-2.60 (3H, m), 1.80-1.59 (4H,m), 1.33-1.19 (6H, m). HPLC: t_(R)=13.44 min. MS: [M+H]⁺ 707

EXAMPLE 51N-[2-[4-(2-(R)-Amino-5-guanidino-pentanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamide

¹H NMR (DMSO-d₆) δ: 8.72 (2H, brs), 8.32-8.42 (1H, brs), 8.16-8.22 (3H,brs), 8.17 (1H, d), 7.82 (1H, d), 7.71 (1H, brs), 7.76-6.89 (7H, m),5.58 (2H, s), 4.49 (1H, brs), 3.13 (1H, brs), 1.63-1.77 (2H, brs),1.44-1.61 (2H, brs), 1.24 (6H, s). HPLC: t_(R)=7.45 min. MS: [M+H]⁺ 709.

EXAMPLE 52N-[2-[4-(3-(S)-Amino-6-guanidino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamide

¹H NMR (DMSO-d₆) δ: 8.94 (2H, s), 8.71(1H, s), 8.31 (1H, s), 8.08 (1H,d), 7.82 (1H, d), 7.75 (3H, brs), 7.63-7.45 (5H, m), 7.44 (1H, d),7.35-6.60 (4H, m), 5.67 (2H, s), 3.10 (2H, m), 2.82 (2H, m), 2.63 (3H,s), 1.63-1.49 (4H, m), 1.24 (6H, s).

HPLC: t_(R)=7.79 min. MS: [M+H]⁺ 721

EXAMPLE 53N-[2-[4-(3-(S)-Amino-7-guanidino-heptanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamide

¹H NMR (DMSO-d₆) δ: 8.95 (2H, s), 8.59 (1H, s), 8.30 (1H, brs), 8.06(1H, d), 7.82 (1H, d), 7.75 (3H, brs), 7.65-7.38 (6H, m), 7.37-6.73 (3H,m), 5.68 (2H, s), 3.07 (2H, m), 2.80 (1H, m), 2.67 (1H, m), 2.63 (3H,s), 1.63-1.29 (6H, m), 1.29-1.18 (6H, s).

HPLC: t_(R)=7.90 min. MS: [M+H]⁺ 735

EXAMPLE 54N-{2-[4-(4-2-(guanidino)ethyl]piperazin-1-ylacetyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamide

¹H NMR (DMSO-d₆) δ: 8.62 (1H, brs), 8.25 (1H, brs), 8.23 (1H, d), 8.05(1H, d), 7.76 (1H, d), 7.60-7.33 (5H, m), 7.18-6.99 (5H, brs), 5.68 (2H,s), 4.06 (2H, brs), 3.58 (2H, brs), 3.34 (2H, m), 3.17 (4H, brs), 2.89(4H, brs), 2.73 (2H, m), 2.67 (3H, s), 1.31 (6H, s). HPLC: t_(R)=7.75min. MS: [M+H]⁺ 762

EXAMPLE 55N-[1-[4-(2-(S)-Amino-5-guanidino-pentanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) d: 8.64 (1H, s), 8.26 (1H, d), 8.15 (2H, brs), 8.05(1H, d), 7.83 (1H, d), 7.66-7.36 (5H, m), 7.34-6.85 (5H, brs), 5.68 (2H,s), 4.50 (1H, brs), 3.14 (2H, s), 2.63 (3H, s), 2.07-1.38 (12H, m).HPLC: t_(R)=10.63 min. MS: [M+H]⁺ 733

EXAMPLE 56N-[1-[4-(2-(S)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.64 (1H, s), 8.28 (1H, brs), 8.14 (2H, brs), 8.03(1H, d), 7.83 (1H, d), 7.63-7.38 (5H, m), 7.37-6.82 (5H, m), 5.68 (2H,s), 4.47 (1H, brs), 3.07 (2H, m),), 2.62 (3H, s), 2.04-1.90 (2H, brs),1.84-1.59 (4H, brs), 1.56-1.37 (8H, m). HPLC: t_(R)=10.98 min. MS:[M+H]⁺ 747

ESEMPIO 57N-[1-[4-(2-(S)-Amino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 9.50 (1H, brs), 8.65 (1H, s), 8.26 (1H, d),8.22-8.11 (2H, m), 8.03 (1H, d), 7.83 (1H, d), 7.62-7.35 (5H, m), 5.68(2H, s), 4.56-4.41 (1H, brs), 3.09-2.92 (2H, brs),), 2.77 (6H, s), 2.62(3H, s), 2.07-1.24 (16H, m). HPLC: t_(R)=8.19 min. MS: [M+H]⁺ 733

EXAMPLE 58N-[1-[4-(2-(S)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.65 (1H, s), 8.14 (3H, brs), 8.04 (1H, d), 7.83(1H, d), 7.81-7.44 (5H, m), 7.39-6.76 (3H, s), 5.50 (2H, s), 4.46 (1H,brs), 3.07 (2H, m), 2.72 (3H, s), 2.67 (3H, s), 2.03-1.91 (2H, m),1.80-1.61 (4H, m), 1.53-1.25 (10H, m). HPLC: t_(R)=8.80 min. MS: [M+H]⁺761

EXAMPLE 59N-[1-[4-(2-(S)-Amino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 9.44 (1H, brs), 8.64 (1H, s), 8.23-8.10 (3H, brs),8.03 (1H, d), 7.83 (1H, d), 7.75 (1H, brs), 7.69-7.33 (8H, m), 5.59 (2H,s), 4.48 (1H, brs), 3.00 (1H, m), 2.78 (6H, s), 2.74-2.58 (4H, m), 2.60(6H, s), 2.06-1.23 (14H, m). HPLC: t_(R)=8.96 min. MS: [M+H]⁺ 747

EXAMPLE 60(R)—N-[4-(2-(S)-amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.60 (1H, s), 8.13 (3H, brs), 8.06 (1H, d), 7.82(1H, d), 7.79-6.70 (8H, m), 5.59 (2H, s), 4.46 (1H, brs), 4.33-3.34 (8H,m), 3.07 (2H, m), 2.71 (3H, s), 2.56 (3H, s), 1.86-1.20 (8H, m), 1.09(3H, s), 0.69 (3H, t).HPLC: t_(R)=8.77 min. MS: [M+H]⁺ 749

EXAMPLE 61(R)—N-[1-[4-(2-(S)-Amino-6-dimethylamino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 9.43 (1H, s), 8.60 (1H, s), 8.15 (3H, brs), 8.05(1H, d), 7.82 (1H, d), 7.78-7.31 (4H, m), 5.58 (2H, s), 4.47 (1H, s),3.74 (8H, m), 3.00 (2H, m), 2.77 (6H, s), 2.68 (3H, s), 2.60 (3H, s),1.87-1.53 (8H, m), 1.10 (3H, s), 0.71 (3H, t). HPLC: t_(R)=8.53 min. MS:[M+H]⁺ 735

EXAMPLE 62N-{2-[4-(4-2(Guanidino)ethyl]piperazin-1-ylacetyl)-piperazin-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetetra trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.45 (1H, s), 8.02 (1H, d), 7.77 (1H, d), 7.76-7.33(4H, m), 7.25-7.12 (4H, brs), 5.68 (2H, s), 4.25-4.10 (2H, brs),3.75-2.76 (16H, m), 2.75 (3H, s), 2.70 (3H, s), 2.10-0.90-(8H, m).

HPLC: t_(R)=8.90 min. MS: [M+H]⁺ 802

EXAMPLE 63N-[1-[4-(2-(R)-Amino-6-amino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.42 (1H, s), 8.09 (3H, brs), 8.02 (1H, d), 7.78(1H, d), 7.72 (1H, d), 7.70 (3H, brs), 7.51 (1H, t), 7.39 (1H, d), 7.34(1H, s), 5.53 (2H, s), 4.41 (1H, brs), 3.84-3.46 (8H, m), 2.80 (2H,brs), 2.68 (3H, s), 2.62 (3H, s), 1.85-1.23 (14H, m). HPLC: t_(R)=8.58min. MS: [M+H]⁺ 719

EXAMPLE 64N-[1-[4-(2-(R)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

hu 1H NMR (DMSO-d₆) δ: 8.42 (1H, s), 8.08 (3H, brs), 8.02 (1H, d), 7.79(1H, d), 7.74 (1H, d), 7.50-7.34 (3H, m), 7.07-6.93 (4H, brs), 5.54 (2H,s), 4.42 (1H, brs), 3.73 (8H, m), 3.11 (2H, m), 2.68 (3H, s), 2.63 (3H,s), 2.08-1.22 (14H, m). HPLC: t_(R)=8.74 min. MS: [M+H]⁺ 761

EXAMPLE 65 N-[2-[4-(3-(S)-Amino-6-guanidino-hexanoyl)-piperazin-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide tristrifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.44 (1H, s), 8.02 (1H, d), 7.79 (1H, d), 7.77-7.67(3H, m), 7.50 (1H, t), 7.43 (1H, t), 7.37 (1H, d), 7.32 (1H, brs),7.10-6.90 (4H, brs), 5.61 (2H, s), 3.77-3.41 (9H, m), 3.02 (2H, m),2.79-2.68 (2H, m), 2.66 (3H, s), 2.59 (3H, s), 2.06-1.37 (12H, m). HPLC:t_(R)=9.02 min. MS: [M+H]⁺ 761

EXAMPLE 66N-[2-[4-(3-(S)-Amino-6-dimethylamino-hexanoyl)-piperazin-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 9.47 (1H, brs), 8.61 (1H, s), 8.03 (1H, d), 7.82(1H, d), 7.81 (3H, s), 7.68 (1H, d), 7.51 (1H, t), 7.39 (1H, d), 7.32(1H, brs), 5.55 (2H, s), 3.52 (8H, m), 3.03-2.84 (2H, brs), 2.76 (3H,s), 2.63 (3H, s), 2.56 (3H, s), 2.03-1.34 (10H, m). HPLC: t_(R)=8.85min. MS: [M+H]⁺ 747

EXAMPLE 67N-[1-[4-(6-Guanidino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidebis trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.44 (1H, s), 8.02 (1H, d), 7.79 (1H, d), 7.76-7.32(5H, m), 7.05-6.84 (4H, brs), 5.55 (2H, s), 3.66-3.47 (8H, m), 3.10 (2H,m), 2.68 (3H, s), 2.52 (3H, s), 2.38-2.32 (2H, m), 2.08-1.23 (14H, m).HPLC: t_(R)=10.17 min. MS: [M+H]⁺ 746

EXAMPLE 68N-[2-[4-(2-(S)-Amino-6-amino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.72 (1H, m), 8.37-8.28 (1H, d), 8.18-8.11 (3H, d),8.07 (1H, d), 7.83 (1H, d), 7.76-7.67 (3H, brs), 7.64-7.40 (4H, m), 5.49(2H, s), 4.45 (1H, s), 3.65-3.43 (8H, m), 2.83-2.72 (2H, m), 2.65 (3H,s), 1.77-1.31 (6H, m), 1.25 (6H, s). HPLC: t_(R)=7.30 min. MS: [M+H]⁺679

EXAMPLE 69N-[2-[4-(2-(S)-Guanidino-6-guanidino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.44 (1H, s), 8.24 (1H, d), 8.06 (1H, d), 7.79 (1H,d), 7.58 (1H, d), 7.61-7.34 (4H, m), 5.65 (2H, s), 4.78 (1H, m),3.95-3.46 (8H, m), 3.11 (2H, m), 2.65 (3H, s), 1.79-1.31_(6H, m), 1.28(6H, s). HPLC: t_(R)=8.04 min. MS: [M+H]⁺ 763

EXAMPLE 70(R)—N-[4-(3-(S)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.29 (1H, s), 8.64 (1H, d), 7.78 (1H, d), 7.77-7.69(3H, m), 7.56-7.31 (4H, m), 7.10-6.96 (4H, brs), 5.64 (2H, s), 3.74-3.14(11H, m), 2.86-2.76 (2H, m), 2.68 (3H, s), 2.62 (3H, s), 1.91-1.53 (6H,m), 1.14 (6H, s). HPLC: t_(R)=9.00 min. MS: [M+H]⁺ 749

EXAMPLE 71(R)—N-{2-[4-(4-2(Guanidino)ethyl]piperazin-1-ylacetyl)-piperazin-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetetra trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.32 (1H, s), 8.05 (1H, d), 7.78 (1H, d), 7.76-7.33(5H, m), 7.20-7.07 (4H, m), 5.65 (2H, s), 4.24-4.03 (2H, brs), 3.65-3.68(8H, m), 3.00-2.77 (4H, m), 2.59 (3H, s), 2.54 (3H, s), 1.92-1.77 (1H,m), 1.75-1.63 (1H, m), 1.13 (3H, s), 0.72 (3H, s).

HPLC: t_(R)=8.94 min. MS: [M+H]⁺ 790

EXAMPLE 72(R)—N-[4-(3-(S)-Amino-6-amino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.58 (1H, s), 8.06 (1H, d), 7.87-7.47 (12H, m), 5.60(2H, m), 2.84-2.57 (11H, m), 1.87-1.64 (2H, m), 1.66-1.58 (4H, brs),1.09 (3H, brs), 0.69 (3H, t). HPLC: t_(R)=8.72 min. MS: [M+H]⁺ 707

EXAMPLE 73(R)—N-[4-(3-(S)-Guanidino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.30 (1H, s), 8.05 (1H, d), 7.77 (1H, d), 7.72 (1H,d), 7.58-7.31 (5H, m), 7.14-6.88 (8H, brs), 5.64 (2H, s), 3.97-3.86 (1H,brs), 3.79-3.44 (8H, m), 3.17-3.10 (3H, m), 2.67 (3H, s), 2.66 (2H, m),2.66 (2H, m), 2.61 (3H, s), 1.90-1.58 (2H, m), 1.58-1.46 (4H, brs), 1.13(3H, s), 0.72 (3H, t). HPLC: t_(R)=9.22 minMS: [M+H]⁺⁺ 396

EXAMPLE 74 (R)—N-[4-(3-(S)-Amino-6-dimethylamino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 9.48-9.37 (1H, brs), 8.57 (1H, s), 8.05 (1H, d),7.82 (1H, d), 7.83-7.26 (7H, m), 5.58 (1H, m), 3.83-3.56 (8H, m),3.09-2.97 (2H, m), 2.77 (6H, s), 2.67 (6H, s), 1.87-1.48 (6H, m), 1.08(3H, s), 0.70 (3H, t). HPLC: t_(R)=8.81 min. MS: [M+H]⁺ 735

EXAMPLE 75(S)—N-[4-(2-(S)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.32 (1H, s), 8.13-8.06 (3H, brs), 8.04 (1H, d),7.78 (1H, d), 7.76-7.36 (5H, m), 7.09-6.93 (4H, brs), 5.64 (2H, s),4.47-4.38 (1H, brs), 3.96-3.75 (8H, m), 3.12 (2H, m), 2.70 (3H, s), 2.64(3H, s), 1.91-1.32 (8H, m), 1.14 (3H, s), 0.72 (3H, t). HPLC: t_(R)=8.64min.MS: [M+H]⁺ 749

EXAMPLE 76(S)—N-[4-(3-(S)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.32 (1H, s), 8.11-8.03 (3H, brs), 8.04 (1H, d),7.78 (1H, d), 7.71 (1H, d), 7.50 (1H, t), 7.39 (1H, t), 7.32 (1H, brs),7.06-6.90 (4H, brs), 5.63 (2H, s), 4.47-4.38 (1H, brs), 3.94-3.48 (8H,m), 3.11 (2H, m), 2.67 (3H, s), 2.59 (3H, s), 1.78-1.32 (6H, m), 1.13(3H, s), 0.72 (3H, t). HPLC: t_(R)=8,94 min. MS: [M+H]⁺ 749

EXAMPLE 772,4-Dichloro-N-{1-[4-(3(S),6-diamino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl}-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.62 (1H, s), 8.04 (1H, d), 7.90-7.32 (12H, m), 5.59(2H, s), 3.58-3.41 (8H, m), 2.86-2.56 (9H, m), 2.03-1.21 (12H, m). HPLC:t_(R)=8.79 min. MS: [M+H]⁺ 719

EXAMPLE 782,4-Dichloro-N-{1-[4-(3(S),6-diguanidino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl}-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide tristrifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.60 (1H, s), 8.03 (1H, d), 7.82 (1H, d), 7.78-6.72(15H, m), 5.57 (2H, s), 3.95-3.83 (1H, brs), 3.15-2.56 (4H, m), 2.68(6H, s), 2.03-1.91 (2H, m), 1.79-1.67 (2H, m), 1.54-1.36 (8H, m).

HPLC: t_(R)=9.28 min. MS: [M+H]⁺ 803

EXAMPLE 79 Compound of General Formula (I) with R₄═R₅═CH₃, X═Cl, R₁═H,B═

R₁₃═—COY, Y═

Y₁═NR₁₄R₁₈R₁₉, T=NR₇R₈, p=4, R₁₄═R₁₈═R₁₉═CH₃, R₇═R₈═H

N-{1-[4-(2-(S)-Amino-6-trimethylammonium-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.66 (1H, s), 8.27-8.12 (3H, brs), 8.04 (1H, d),7.84 (1H, d), 7.81-7.37 (4H, m), 5.60 (2H, s), 4.60-4.42 (1H, brs),3.70-3.42 (8H, m), 3.24 (2H, m), 3.15 (9H, s), 2.75 (3H, s), 2.67 (3H,s), 2.04-1.93 (2H, m), 1.82-1.22 (14H, m). HPLC: t_(R)=8.61 min. MS:[M]⁺ 761

EXAMPLE 80N-(1-{4-[3-(S),6-Bis-(N′,N″-dicyclohexyl-guanidino)-hexaoyl]-piperazine-1-carbonyl}-cyclopentyl)-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzensulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.59 (1H, s), 8.02 (1H, d), 7.82 (1H, d), 7.77-6.88(10H, m), 5.58 (2H, s), 3.52-3.36 (8H, m), 3.26-3.14 (2H, m), 2.82-2.57(6H, m), 2.04-1.90 (2H, m), 1.87-1.00 (52H, m).

HPLC: t_(R)=16.91 min. MS: [M+H]⁺ 1131

EXAMPLE 81N-{1-[4-(2-(S)Amino-3-piperidin-4-yl-propionyl)-piperazine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.65-8.45 (1H, brs), 8.40 (1H, s), 8.38-8,20 (3H,m), 8.02 (1H, d), 7.82 (1H, m), 7.78 (3H, m), 7.72 (1H, d), 5.58 (2H,s), 4.40 (1H, m), 3.80-3.52 (8H, m), 3.40-3.25 (2H, m), 2.89 (6H, s),2.20-1.28 (15H, m). HPLC: t_(R)=8.85 min. MS: [M+H]⁺ 745

EXAMPLE 82N-{1-[4-(2-Trimethylammonium-acetyl)-piperazine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidebis trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.27 (1H, s), 8.03 (1H, d), 7.77 (1H, d), 7.74-7.37(4H, m), 5.69 (2H, s), 4.51 (2H, s), 3.75-3.47 (8H, m), 3.29 (9H, s),2.70 (3H, s), 2.66 (3H, s), 2.11-2.01 (2H, m), 1.84-1.73 (2H, m),1.53-1.43 (4H, m). HPLC: t_(R)=9.64 min. MS: [M]⁺ 690

EXAMPLE 83N-{1-[4-(4-Trimethylammonium-butanoyl)-piperazine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidebis trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.25 (1H, s), 8.02 (1H, d), 7.82-7.70 (2H, m),7.58-7.33 (3H, m), 5.68 (2H, s), 3.64 (4H, brs), 3.55 (4H, brs),3.37-3.28 (2H, m), 3.10 (9H, s), 2.69 (3H, s), 2.65 (3H, s), 2.50-2.44(2H, m), 2.11-1.73 (6H, m), 1.55-1.42 (4H, brs). HPLC: t_(R)=9.71 min.MS: [M]⁺ 718

EXAMPLE 84N-{1-[4-(3(R)-Hydroxy-4-trimethylammonium-butanoyl)-piperazine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidebis trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.27 (1H, s), 8.02 (1H, d), 7.77 (1H, d), 7.76-7.33(4H, m), 5.68 (2H, s), 4.55-4.47 (1H, m), 3.69-3.49 (8H, m), 3.40 (2H,s), 3.18 (9H, s), 2.58 (3H, s), 2.54 (3H, s), 2.11-2.00 (2H, m),1.84-1.73 (2H, m), 1.51-1.43 (4H, m). HPLC: t_(R)=9.44 min. MS: [M]⁺ 734

EXAMPLE 85N-[1-[4-(2-(S)-Dimethylamino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 9.40 (1H, brs), 8.32 (1H, s), 8.02 (1H, d), 7.77(1H, d), 7.76-7.33 (4H, m), 5.68 (2H, s), 4.48 (1H, brs), 3.89-3.45 (8H,m), 3.18-3.04 (2H, m), 2.81 (3H, s), 2.79 (3H, s), 2.68 (3H, s), 2.64(3H, s), 2.09-1.28 (10H, m). HPLC: t_(R)=8.65 min. MS: [M+H]⁺ 775

EXAMPLE 86 {5-[(1-{1-[2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzensulfonylamino]-cyclopentanecarbonyl}-piperidin-4-ylmethyl)-dimethyl-ammonium]-pentyl}-trimethyl-ammoniumtris trifluoroacetate

HPLC: t_(R)=7.60 min. MS: [M+H]⁺ 775.9

EXAMPLE 87{5-[(1-{1-[2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzensulfonylamino]-cyclopentanecarbonyl}-piperidine-4-carbonyl)-amino]-pentyl}-trimethyl-ammoniumbis trifluoroacetate salt

HPLC: t_(R)=8.20 min. MS: [M+H]⁺ 761.8

EXAMPLE 88N-[1-[4-(2-(S)-Trimethylammonium-6-trimethylammonium-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.32 (1H, s), 8.02 (1H, d), 7.78 (1H, d), 7.73 (1H,d), 7.59-7.31 (3H, m), 5.68 (2H, s), 4.68-4,60 (1H, m), 4.01-3.56 (8H,m), 3.36-3.28 (2H, m), 3.22 (9H, s), 3.08 (9H, s), 2.68 (3H, s), 2.63(3H, s), 2.13-1.43 (14H, m). HPLC: t_(R)=8.80 min. MS: [M]⁺⁺ 402

EXAMPLE 89N-[1-[4-(2-(R)-Trimethylammonium-6-trimethylammonium-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.30 (1H, s), 8.02 (1H, d), 7.81-7.69 (2H, m), 7.52(1H, t), 7.43-7.34 (2H, m), 5.67 (2H, s), 4.64 (1H, dd), 3.35-3.28 (1H,m), 3.22 (9H, s), 3.07 (9H, s), 2.68 (3H, s), 2.64 (3H, s), 2.12-1.97(3H, m), 1.84-1.72 (3H, m), 1.54-1.43 (4H, m), 1.41-1.27 (1H, m),1.27-1.13 (1H, m).

HPLC: t_(R)=7.26 min. MS: [M]⁺⁺ 402

EXAMPLE 90N-[1-[4-(2-(S)-Trimethylammonium-6-amino-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.35 (1H, s), 8.07 (1H, d), 8.01-7.94 (1H, m), 7.87(2H, s), 7.80 (1H, d), 7.77-7.59 (3H, brs), 5.74 (2H, s), 4.65-4.58 (1H,m), 3.98-3.51 (8H, m), 3.22 (9H, s), 2.91 (6H, s), 2.82-2.80 (2H, m),2.13-1.41 (14H, m). HPLC: t_(R)=8.64 min. MS: [M]⁺ 761

EXAMPLE 91N-{1-[4-(6-Trimethylammonium-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidebis trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.30 (1H, s), 8.07 (1H, d), 8.02-7.94 (1H, m),7.91-7.76 (4H, m), 5.74 (2H, s), 3.67-3.50 (8H, m), 3.34-3.26 (2H, m),3.07 (9H, s), 2.92 (3H, s), 2.68 (3H, s), 2.91 (3H, s), 2.43-2.36 (2H,m), 2.12-1.33 (14H, m). HPLC: t_(R)=9.99 min. MS: [M]⁺ 746

EXAMPLE 92N-(6-Amino-hexyl)-4-{2-[2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-2-methyl-propionyl}-piperazine-1-carboxamidine

¹H NMR (DMSO-d₆) δ: 8.71 (1H, s), 8.37-8.29 (1H, m), 8.07 (1H, d), 7.82(1H, d), 7.79-7.64 (5H, m), 7.64-7.41 (3H, m), 5.58 (2H, s), 3.22-3.14(2H, m), 2.84-2.72 (2H, m), 2.65 (3H, s), 1.59-1.46 (4H, m), 1.35-1.27(4H, m), 1.24 (6H, s). MS: [M+H]⁺ 692; HPLC: t_(R)=9.16 min

EXAMPLE 93 N-[2-(3-Amino-propylamino)-ethyl]-4-{2-[2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-2-methyl-propionyl}-piperazine-1-carboxamidine

¹H NMR (DMSO-d₆) δ: 8.92-8.82 (2H, m), 8.73 (1H, s), 8.39-8.29 (1H,brd), 8.07 (1H, d), 7.98-7.85 (6H, m), 7.82 (1H, d), 7.64-7.41 (4H, m),5.58 (2H, s), 3.18-3.10 (2H, m), 3.10-3.00 (2H, m), 2.94-2.83 (2H, m),2.65 (3H, s), 1.96-1.85 (2H, m), 1.25 (6H, s). HPLC: t_(R)=8.20 min.;MS: [M+H]⁺ 693

EXAMPLE 94N-(3-Amino-propyl)-4-{2-[2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-2-methyl-propionyl}-piperazine-1-carboxamidinebis trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.57 (1H, s), 8.06 (1H, d), 7.89-7.68 (8H, m),7.62-7.38 (3H, m), 5.62 (2H, s), 3.32-3.23 (2H, m), 2.92-2.81 (2H, m),2.69 (3H, s), 2.64 (3H, s), 1.87-1.75 (2H, m), 1.25 (6H, s). HPLC:t_(R)=9.36 min.; MS: [M+H]⁺ 664

EXAMPLE 95N-(6-Amino-hexyl)-4-{1-[2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclopentanecarbonyl}-piperazine-1-carboxamidinebis trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.41 (1H, s), 8.02 (1H, d), 7.78 (1H, d), 7.76-7.59(7H, m), 7.54 (1H, t), 7.43 (1H, d), 7.38 (1H, s), 5.64 (2H, s),3.76-3.65 (4H, m), 3.55-3.47 (4H, m), 3.24-3.15 (2H, m), 2.85-2.75 (2H,m), 2.69 (3H, s), 2.63 (3H, s), 2.08-1.98 (2H, m), 1.82-1.72 (2H, m),1.60-1.51 (3H, m), 1.49-1.42 (3H, m), 1.40-1.24 (4H, m). HPLC:t_(R)=10.54 min.; MS: [M+H]⁺ 732

EXAMPLE 96N-[2-(3-Amino-propylamino)-ethyl]-4-{1-[2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclopentanecarbonyl}-piperazine-1-carboxamidinebis trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.97-8.69 (1H, brs), 8.42 (1H, s), 8.02 (1H, d),7.96-7.74 (5H, m), 7.78 (1H, d), 7.72 (1H, d), 7.51 (1H, t), 7.39 (1H,d), 7.34 (1H, s), 5.64 (2H, s), 3.83-3.68 (4H, m), 3.61-3.51 (4H, m),3.11-3.02 (2H, m), 2.97-2.88 (2H, m), 2.67 (3H, s), 2.61 (3H, s),2.07-1.89 (4H, m), 1.81-1.71 (2H, m), 1.52-1.42 (4H, m). HPLC:t_(R)=9.34 min.; MS: [M+H]⁺ 733

EXAMPLE 97N-[2-(4-{1-[2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclopentanecarbonyl}-piperazin-1-yl)-ethyl]-4-methyl-piperazine-1-carboxamidinebis trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.64 (1H, s), 8.27-8.07 (2H, m), 8.03 (1H, d), 7.82(1H, d), 7.79-7.72 (1H, m), 7.70-7.40 (2H, m), 5.60 (2H, s), 2.84 (3H,s), 2.76-2.60 (5H, m), 2.03-1.92 (2H, m), 1.79-1.68 (2H, m), 1.48-1.39(4H, m).

HPLC: t_(R)=7.04 min; MS: [M+H]⁺ 759

EXAMPLE 982,4-Dichloro-N-{1-[4-(2(R),6-diamino-hexyl)-piperazine-1-carbonyl]-cyclopentyl}-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetetra trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.53 (1H, s), 8.03 (1H, d), 7.87-7.40 (8H, m), 7.83(1H, d), 5.60 (2H, s), 2.83-2.56 (8H, m), 2.01-1.92 (2H, m), 1.78-1.64(2H, m), 1.60-1.32 (10H, m). HPLC: t_(R)=7.00 min; MS: [M+H]⁺ 705

EXAMPLE 992,4-Dichloro-N-{1-[4-(2(R),6-diguanidino-hexyl)-piperazine-1-carbonyl]-cyclopentyl}-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetetrahydrochloride

¹H NMR (DMSO-d₆) δ: 8.81-8.65 (2H, brs), 8.30 (1H, s), 8.03 (1H, d),7.88-7.63 (3H, m), 7.58-6.91 (13H, m), 5.66 (2H, s), 2.75-2.58 (7H, m),2.14-1.94 (2H, m), 1.84-1.08 (15H, m). HPLC: t_(R)=7.30 min; MS: [M+H]⁺789

EXAMPLE 1002,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-N-{1-[4-(2-piperazin-1-yl-ethyl)-piperazine-1-carbonyl]-cyclopentyl}-benzenesulfonamidetetra trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.75-8.62 (3H, m), 8.04 (1H, d), 7.93-7.56 (4H, m),5.63 (2H, s), 3.39-3.27 (4H, m), 3.19-3.09 (3H, m), 3.04-2.97 (1H, m),2.87-2.62 (11H, m), 2.04-1.92 (2H, m), 1.77-1.52 (3H, m), 1.49-1.36 (4H,m).

HPLC: t_(R)=7.30 min; MS: [M+H]⁺ 703

EXAMPLE 1012,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-N-{1-[4-(2-piperidin-4-yl-ethyl)-piperazine-1-carbonyl]-cyclopentyl}-benzenesulfonamide

¹H NMR (DMSO-d₆) δ: 8.68 (1H, s), 8.61-8.47 (1H, m), 8.34-8.16 (1H, m),8.03 (1H, d), 7.93-7.40 (3H, m), 7.84 (1H, d), 7.34-7.17 (2H, m), 5.61(2H, s), 4.58-4.40 (2H, m), 3.35-3.23 (2H, m), 3.22-3.09 (2H, m),3.06-2.60 (9H, m), 2.08-1.94 (2H, m), 1.88-1.50 (9H, m), 1.50-1.37 (4H,m), 1.37-1.18 (3H, m). HPLC: t_(R)=7.50 min; MS: [M+H]⁺ 702

EXAMPLE 102{3-[(4-{1-[2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclopentanecarbonyl}-piperazine-1-carboximidoyl)-amino]-propyl}-trimethyl-ammoniumtris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.37-8.26 (1H, m), 8.07-7.98 (1H, m), 7.83-7.66 (4H,m), 7.56-7.46 (1H, m), 7.44-7.31 (2H, m), 5.73-5.64 (2H, m), 3.82-3.71(4H, m), 3.62-3.52 (5H, m), 3.41-3.26 (4H, m), 3.18-3.06 (9H, m),2.74-2.60 (6H, m), 2.14-1.96 (5H, m), 1.85-1.73 (2H, m), 1.56-1.43 (4H,m).

HPLC: t_(R)=9.90 min; MS: [M]⁺ 732

EXAMPLE 103 4-{1-[2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclopentanecarbonyl}-N-(3-dimethylamino-propyl)-piperazine-1-carboxamidinetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 9.78-9.40 (1H, brs), 8.35-8.22 (1H, m), 8.06-7.94(1H, m), 7.82-7.57 (5H, m), 7.57-7.46 (1H, m), 7.46-7.32 (2H, m),5.71-5.63 (2H, m), 3.80-3.66 (4H, m), 3.59-3.48 (4H, m), 3.36-3.26 (2H,m), 3.15-3.06 (2H, m), 2.86-2.78 (6H, m), 2.73-2.58 (6H, m), 2.12-1.98(2H, m), 1.98-1.87 (2H, m), 1.83-1.72 (2H, m), 1.54-1.41 (4H, m). HPLC:t_(R)=10.14 min; MS: [M+H]⁺ 718

EXAMPLE 104N-(1-{4-[(5-Amino-pentylamino)-methyl]-piperidine-1-carbonyl}-cyclopentyl)-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.52 (1H, s), 8.47-8.32 (2H, m), 8.03 (1H, d), 7.81(1H, d), 7.78-7.29 (7H, m), 5.58 (2H, s), 4.44-4.34 (2H, m), 3.06-2.55(12H, m), 2.02-1.84 (3H, m), 1.82-1.69 (2H, m), 1.68-1.48 (4H, m),1.48-1.30 (5H, m). HPLC: t_(R)=7.39 min; MS: [M+H]⁺ 704

EXAMPLE 105N-{1-[4-(4-Amino-piperidin-1-ylmethyl)-piperidine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 9.62-9.24 (1H, m), 8.53 (1H, s), 8.20-7.99 (2H, m),8.03 (1H, d), 7.86-7.26 (3H, m), 7.82 (1H, d), 5.59 (2H, s), 4.47-4.31(2H, m), 3.11-2.92 (4H, m), 2.84-2.57 (6H, m), 2.15-1.88 (5H, m),1.88-1.51 (5H, m), 1.51-1.32 (4H, m). HPLC: t_(R)=7.22 min; MS: [M+H]⁺702

EXAMPLE 1062,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-N-(1-{4-[(5-methylamino-pentylamino)-methyl]-piperidine-1-carbonyl}-cyclopentyl)-benzenesulfonamidetris trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.32 (2H, brs), 8.17 (1H, s), 8.01 (1H, d),7.79-7.70 (2H, m), 7.50 (1H, t), 7.37 (1H, d), 7.33 (1H, s), 5.66 (2H,s), 4.42-4.33 (2H, m), 2.98-2.74 (8H, m), 2.67 (3H, s), 2.65-2.57 (5H,m), 2.10-1.88 (3H, m), 1.85-1.74 (4H, m), 1.71-1.57 (4H, m), 1.53-1.14(8H, m).

HPLC: t_(R)=7.56 min; MS: [M+H]⁺ 718

EXAMPLE 107[4-(S)-Amino-6-(4-{1-[2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclopentanecarbonyl}-piperazin-1-yl)-6-oxohexyl]-trimethylammoniumbis trifluoroacetate

¹H NMR (DMSO-d₆) δ: 8.27 (1H, s), 8.08-7.99 (1H, m), 7.95-7.72 (4H, m),7.59-7.51 (1H, m), 7.47-7.37 (2H, m), 5.68 (2H, m), 3.76-3.48 (8H, m),3.37-3.24 (2H, m), 3.13-3.06 (9H, m), 2.92-2.79 (1H, m), 2.76-2.63 (7H,m), 2.13-1.99 (2H, m), 1.93-1.74 (3H, m), 1.73-1.60 (2H, m), 1.56-1.42(4H, m). HPLC: t_(R)=10.26 min. MS: [M+H]⁺ 761

Biological Activity

The evaluation of the B2 receptor affinity of the compounds of thepresent invention was carried out with studies of binding to the humanB2 receptor expressed in human fibroblasts W138, following the proceduredescribed by Phagoo et al., Br. J. Pharmacol. (1996) 119: 863-868. Inthe following the binding values are reported expressed as pKi.

The in vivo activity of the compounds of the present invention wasevaluated as effectiveness in inhibiting BK-induced bronchospasm in theguinea pig, following the procedure described by Tramontana et al., J.Pharmacol. Exp. Therap., 296:1051-1057, 2001. The compounds of thepresent invention show higher potency and longer-lasting action thanthose of molecules of a similar class which however do not containalpha,alpha dialkyl amino acids. Compound Compound (Example N) pKi(Example N) pKi 25 9.27 26 9.3 31 9.4 29 9.2 30 9.1 20 9.2 45 9.2 46 9.348 9.2 51 9.4 57 9.0 59 9.0 93 9.0 61 9.3 94 9.0 62 9.0 64 9.2 65 9.1 669.1 67 9.1 95 9.3 96 9.1 68 9.0 70 9.2 71 9.4 72 9.4 73 9.2 74 9.1 989.2 80 9.2 81 9.2 38 9.3 39 9.0 100 9.4 105 9.0 82 9.2 83 9.4 84 9.2 859.3 106 9.4 86 9.4 107 9.7 88 9.7 90 9.9 91 9.3 40 9.7 41 9.3 42 9.4 439.4 44 10.1 79 9.2

1. Compounds of general formula (I):

in which R₁ is a hydrogen atom or a C₁-C₄ alkyl group; R₂ and R₃, whichcan be the same or different, are a C₁-C₄ alkyl group, or R₂ and R₃,together with the carbon atom which they are linked to, form a cyclicaliphatic group having 3 to 7 carbon atoms or a heterocyclic aliphaticgroup having 3 to 7 atoms, one or two of which are selected from thegroup N, O, S and the others being C atoms; R₄ and R₅, which can be thesame or different, are a hydrogen atom or a C₁-C₄ alkyl group; X isselected from the group consisting of halogen, OR₁, SR₁, CN, C₁-C₄alkyl; B has at least one amino group with basic characteristics or atetraalkylammonium group and can be selected from the group consistingof: NR₆(CH₂)nNHCOY, NR₆(CH₂)_(n)N(R₆)—Y, NR₆(CH₂)_(n)N(Y)₂, NR₆Y, N(Y)₂,N(Y)(CH₂)_(p)Y₁ and from the residues:

R₆ is a hydrogen atom, C₁-C₆ alkyl, n=1-12 and Y is selected from:hydrogen, (CH₂)pY₁, (CH₂)_(p)NR₆Y₁, (CH₂)_(p)N(Y₁)₂, NR₅R₆,—NR₆(CH₂)_(q)Y₁ or from the following residues:

T is selected from the group of —NR₇R₈, —NR₁₄R₁₈R₁₉, —OR₆; R₇ and R₈,which can be the same or different, are a hydrogen atom, a C₁-C₄ alkylgroup, a cyclohexyl group, or NR₇R₈ together are a group selected from:i) guanidine optionally substituted with 1 or 2 C₁-C₄ alkyl orcyclohexyl groups, ii) a 5-7 membered nitrogen heterocycle optionallycontaining another heteroatom selected from O, N, S; Y₁ is selected fromthe group consisting of NR₇R₈, NR₁₄R₁₈R₁₉ or from the followingresidues:

Z is selected from the group consisting of H, C₁-C₆ alkyl, OR₆, SR₆,CF₃, OCOR₆, COR₁₀, NHCOR₆, SO₂R₆, SOR₆, CO₂R₆, N(R₆)₂, Cl, Br, NO₂, NH₂,CN, F, imidazole, phenyl, amidine, guanidine, guanidyl-methyl; R₉ isselected from the group consisting of hydrogen, —(CH₂)_(q)-L, wherein Lis selected from the group of —OH, —NR₅R₆, —NR₁₄R₁₈R₁₉, amidineoptionally substituted with 1 or 2 C₁-C₄ alkyl groups, guanidineoptionally substituted with 1 or 2 C₁-C₄ alkyl groups; R₁₀ is selectedfrom the group consisting of OR₆, NR₆R₁₂; R₁₁ is selected from the groupconsisting of hydrogen, —(CH₂)_(q)-L, —(CH₂)_(p)—NR₄—(CH₂)_(q)-L; R₁₂ isa hydrogen atom, C₁-C₆ alkyl, COR₆, R₁₃ is selected from the groupconsisting of H, C₁-C₆ alkyl, —(CH₂)_(p)W(CH₂)_(q)Y₁, Y, —COY, —CH₂—Y;R₁₅ is selected from the group consisting of hydrogen or straight orbranched C₁-C₄ alkyl groups; the —NR₁₆R₁₇ group is a 5-7 memberednitrogen aliphatic heterocycle optionally containing another heteroatomselected from O, S, N; the —NR₁₄R₁₈R₁₉ group is a quaternary ammoniumgroup in which: R₁₄ is selected from the group consisting of straight orbranched C₁-C₄ alkyl groups, R₁₈ and R₁₉, which can be the same ordifferent, are a straight or branched C₁-C₄ alkyl group, or —NR₁₈R₁₉ isa 5-7 membered nitrogen heterocycle optionally containing anotherheteroatom selected from O, N, S. W═CH₂, O, S, NR₄, N(R₄)₂ p=1-6, q=1-6;and the pharmacologically acceptable salts thereof with inorganic ororganic acids selected from the group of: hydrochloric, hydrobromic,hydroiodic, sulfuric, phosphoric, acetic, trifluoroacetic, propionic,oxalic, malic, maleic, succinic, malonic, aspartic, glutamic acids andpossible optical isomers or their mixtures, including the racemates. 2.Compounds as claimed in claim 1, in which R₁ is a hydrogen atom or aC₁-C₄ alkyl group; R₂ and R₃, which can be the same or different, are aC₁-C₄ alkyl group, or R₂ and R₃, together with the carbon atom whichthey are linked to, form a cyclic aliphatic group having 3 to 7 carbonatoms or a heterocyclic aliphatic group having 3 to 7 atoms one or twoof which are selected from the group of N, O, S and the other being Catoms; R₄ and R₅, which can be the same or different, are a hydrogenatom or a C₁-C₄ alkyl group; X is selected from the group consisting ofhalogen, OR₁, SR₁, CN, C₁-C₄ alkyl; B has at least one amino group withbasic characteristics or a tetraalkylammonium and can be selected fromthe group consisting of:

R₆ is a hydrogen atom, C₁-C₆ alkyl; Y is selected from: hydrogen,(CH₂)_(p)Y₁, (CH₂)_(p)NR₆Y₁, (CH₂)_(p)N(Y₁)₂, NR₅R₆, —NR₆(CH₂)_(p)Y₁ orfrom the following residues:

T is selected from the group of —NR₇R₈, —NR₁₄R₁₈R₁₉, —OR₆; R₇ and R₈,which can be the same or different, are a hydrogen atom, a C₁-C₄ alkylgroup, or NR₇R₈ is a group selected from: i) guanidine optionallysubstituted with 1 or 2 C₁-C₄ alkyl groups, cyclohexyl, ii) a 5-7membered nitrogen heterocycle optionally containing another heteroatomselected from O, N, S; Y₁ is selected from the group consisting ofNR₇R₈, NR₁₄R₁₈R₁₉ or from the following residues:

Z is selected from the group consisting of H, C₁-C₆ alkyl, OR₆, SR₆,CF₃, OCOR₆, COR₁₀, NHCOR₆, SO₂R₆, SOR₆, CO₂R₆, N(R₆)₂, C₁, Br, NO₂, NH₂,CN, F, imidazole, phenyl, amidine, guanidine, guanidyl-methyl; R₉ isselected from the group consisting of hydrogen, —(CH₂)q-L, wherein L isselected from the —OH group, —NR₅R₆, —NR₁₄R₁₈R₁₉, amidine optionallysubstituted with 1 or 2 C₁-C₄ alkyl groups, guanidine optionallysubstituted with 1 or 2 C₁-C₄ alkyl groups; R₁₀ is selected from thegroup consisting of OR₆, NR₆R₁₂; R₁₁ is selected from the groupconsisting of hydrogen, —(CH₂)_(q)-L, —(CH₂)_(p)—NR₄—(CH₂)_(q)-L; R₁₂ isa hydrogen atom, C₁-C₆ alkyl, COR₆; R₁₃ is selected from the groupconsisting of H, C₁-C₆ alkyl, —(CH₂)_(p)W(CH₂)_(q)Y₁, Y, —COY, —CH₂—Y;R₁₄ is selected from the group consisting of straight or branched C₁-C₄alkyl groups; R₁₅ is selected from the group consisting of hydrogen orstraight or branched C₁-C₄ alkyl groups; the —NR₁₆R₁₇ group is a 5-7membered nitrogen aliphatic heterocycle optionally containing anotherheteroatom selected from O, S, N; the —NR₁₄R₁₈R₁₉ group is a quaternaryammonium group in which: R₁₄ is selected from the group consisting ofstraight or branched C₁-C₄ alkyl groups, R₁₈ and R₁₉, which can be thesame or different, are a straight or branched C₁-C₄ alkyl group, or—NR₁₈R₁₉ is a 5-7 membered nitrogen heterocycle optionally containinganother heteroatom selected from O, N, S; W═CH₂, O, S, NR₄, N(R₄)₂;p=1-6, q=1-6.
 3. Compounds as claimed in claim 2, of general formula(I), in which: B is selected from the group consisting of the residues:

Y is selected from: (CH₂)_(p)Y₁, (CH₂)_(p)NR₆Y₁, (CH₂)_(p)N(Y₁)₂, NR₅R₆,or from the following residues:

which T is selected from the group of —NR₇R₈, —OR₆ and the othersubstituents are as previously defined.
 4. Compounds as claimed in claim3, in which: R₁ is a hydrogen atom or methyl; R₂ and R₃, which can bethe same or different, are selected from methyl or ethyl, or R₂ and R₃,together with the carbon atom which they are linked to, form a cyclicaliphatic group having 3 to 7 carbon atoms; R₄ and R₅, which can be thesame or different, are a hydrogen or a methyl; X is a chlorine atom; Bis a group selected from:

in which R₁₃ is H, or a Y═Y₁ group in which Y₁ is

R₁₁ is selected from the group consisting of hydrogen, —(CH₂)_(q)-L,—(CH₂)_(p)—NR₄—(CH₂)_(q)-L wherein L is selected from —OH, —NR₅R₆,amidine optionally substituted with 1 or 2 C₁-C₄ alkyl groups, guanidineoptionally substituted with 1 or 2 C₁-C₄ alkyl groups; and the othersubstituents are as previously defined.
 5. Compounds as claimed in claim3, of general formula (I) in which: R₂ and R₃, which can be the same ordifferent, are selected from methyl or ethyl, or R₂ and R₃, togetherwith the carbon atom which they are linked to, form a cyclic aliphaticgroup having 3 to 7 carbon atoms; R₄ and R₅, which can be the same ordifferent, are a hydrogen or a methyl, X is a chlorine atom; B containsat least two amino groups with basic characteristics, in the free orsalified form, and is selected from the group of:

in which R₁₃ is COY, CH₂Y, —(CH₂)_(p)W(CH₂)_(q)Y₁, Y is a group(CH₂)pY₁, or is selected from:

wherein T is selected from —NR₇R₈, —OR₆; R₇ and R₈, which can be can bethe same or different, are a hydrogen atom, a C₁-C₄ alkyl group, orNR₇R₈ is a group selected from: i) guanidine optionally substituted with1 or 2 C₁-C₄ alkyl groups, cyclohexyl, ii) a 5-7 membered nitrogenheterocycle optionally containing another heteroatom selected from O, N,S; Y₁ is selected from the group consisting of —NR₇R₈ and from theresidues

R₉ is selected from the group consisting of hydrogen, —(CH₂)_(q)-L,wherein L is selected from the group —NR₅R₆, amidine optionallysubstituted with 1 or 2 C₁-C₄ alkyl groups, guanidine optionallysubstituted with 1 or 2 C₁-C₄ alkyl groups; and the other substituentsare as previously.
 6. Compounds as claimed in claim 2, of generalformula (I), containing at least one tetralkyl ammonium, in which: R₁ isa hydrogen atom or methyl; R₂ and R₃, which can be the same ordifferent, are selected from methyl or ethyl, or R₂ and R₃, togetherwith the carbon atom which they are linked to, form a cyclic aliphaticgroup having 3 to 7 carbon atoms; R₄ and R₅, which can be the same ordifferent, are a hydrogen or a methyl; X is a chlorine atom; B isselected from the group consisting of NR₆Y, and from the residues:

Y is selected from: Y, COY, (CH₂)_(p)Y₁, NR₆(CH₂)_(q)Y₁ and from theresidues:

T is selected from the group —NR₇R₈, —NR₁₄R₁₈R₁₉, —OR₆; Y₁ is selectedfrom the group consisting of —NR₇R₈, —NR₇R₈R₁₄ or from the followingresidues:

and the other substituents are as previously defined.
 7. Compounds ofgeneral formula (I), as claimed in claim 1, which are:N-[2-[4-(2-(S)-amino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxy-methyl)-benzensulfonamidetrifluoroacetate;N-{2-[4-(6-guanidinohexyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)benzenesulfonamido-2-methyl-propionamidetris trifluoroacetate;4-{2-[2,4-Dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzene-sulfonylamino]-2-methyl-propionyl}-piperazine-1-carboxamidine;N-[2-[4-(2-(S)-amino-5-guanidino-pentanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate;N-{2-[4-(6-aminohexyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate;N-{2-[4-(piperazin-2-yl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate;N-{2-[4-(piperazin-1-ylacetyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzene-sulfonamidebis trifluoroacetate;N-{2-[4-2-(piperidin-4-yl-acetyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzene-sulfonamidebis trifluoroacetate;N-{2-[4-[N-(4-piperidyl)glycyl]-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzene-sulfonamidetris trifluoroacetate;N-{2-[4-(4-(2-aminoethyl)piperazin-1-yl)acetyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetetra trifluoroacetate;N-{2-[4-(3-(R)-Amino-6-guanidino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate;N-{2-[4-(3-(S)-amino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate;N-{2-[4-(3-(S)-amino-7-dimethylamino-heptanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxymethyl)-benzenesulfonamidetris trifluoroacetate;N-(3-Amino-propyl)-4-{2-[2,4-dichloro-3-(2-methyl-quinolin-8-yloxy-methyl)-benzenesulfonylamino]-2-methyl-propionyl}-piperazine-1-carboxamidinetris trifluoroacetate;N-[2-[4-(2-(S)-amino-5-dimethylamino-pentanoyl))-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-8-quinolinoxy-methyl)-benzenesulfonamidetris trifluoroacetate;(S)—N-{2-[1′-(2-Amino-5-guanidino-pentanoyl)-[4,4′]bipiperidinyl-1-yl]-1,1-dimethyl-2-oxo-ethyl}-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamide;2,4-Dichloro-N-(2-{4-[2-(3,5-dimethyl-piperazin-1-yl)-ethyl]-3,5-dimethyl-piperazin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-3-(2-methyl-4a,8a-dihydro-quinolin-8-yloxymethyl)-benzenesulfonamide;N-(2-{4-[4-(2-(S)Amino-5-guanidino-pentanoyl)-piperazin-1-yl]-piperidin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamide;2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfinicacid [1-(4-piperazin-1-yl-piperidine-1-carbonyl)-cyclopentyl]-amide;2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfinicacid(1-{4-[4-(2-S-amino-6-guanidino-hexanoyl)-piperazin-1-yl]-piperidine-1-carbonyl}-cyclopentyl)-amide;2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfinicacid(1-{4-[4-(2-S-amino-5-guanidino-pentanoyl)-piperazin-1-yl]-piperidine-1-carbonyl}-cyclopentyl)-amide;2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfinicacid [1-(4-piperidin-4-yl-piperazine-1-carbonyl)-cyclopentyl]-amide;2,4-Dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfinic acid{2-[4-(2-guanidino-ethyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-amide;2,4-Dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfinic acid(2-{4-[2-S-amino-5-(N′,N″-diethyl-quanidino)-pentanoyl]-piperazin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-amide;2,4-Dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfinic acid(2-{4-[2-R-amino-5-(N′,N″-diethyl-guanidino)-pentanoyl]-piperazin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-amide;(2S)—N-(1-{4-[2-Amino-6-(N′,N″-diethyl-guanidino)-hexanoyl]-piperazine-1-carbonyl}-cyclopentyl)-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide;N-(1-{4-[2-(S)Amino-6-(N′,N″-diethyl-guanidino)-pentanoyl]-piperazine-1-carbonyl}-cyclopentyl)-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide;N-[2-[4-(2-(S)-Amino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide;N-[2-[4-(3-(S)-Amino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide;N-[2-[4-(3-(S)-Amino-6-dimethylamino-heptanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide;N-[2-[4-(2-(S)-Amino-5-guanidino-pentanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide;N-[2-[4-(2-(S)-Amino-6-guanidino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide;N-[2-[4-(2-(S)-Amino-5-dimethylamino-pentanoyl))-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamide;N-[2-[4-(2-(R)-Amino-5-guanidino-pentanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxy-methyl)-benzenesulfonamide;N-[2-[4-(3-(S)-Amino-6-guanidino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxy-methyl)-benzenesulfonamide;N-[2-[4-(3-(S)-Amino-7-guanidino-heptanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxy-methyl)-benzenesulfonamide;N-{2-[4-(4-2(Guanidino)ethyl]piperazin-1ylacetyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamide;N-[1-[4-(2-(S)-Amino-5-guanidino-pentanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-[1-[4-(2-(S)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-[1-[4-(2-(S)-Amino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-[1-[4-(2-(S)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-[1-[4-(2-(S)-Amino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;(R)—N-[4-(2-(S)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;(R)—N-[1-[4-(2-(S)-Amino-6-dimethylamino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-{2-[4-(4-2(Guanidino)ethyl]piperazin-1ylacetyl)-piperazin-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetetra trifluoroacetate;N-[1-[4-(2-(R)-Amino-6-amino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-[1-[4-(2-(R)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-[2-[4-(3-(S)-Amino-6-guanidino-hexanoyl)-piperazin-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-[2-[4-(3-(S)-Amino-6-dimethylamino-hexanoyl)-piperazin-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-[1-[4-(6-Guanidino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzene-sulfonamidebis trifluoroacetate;N-[2-[4-(2-(S)-Amino-6-amino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-[2-[4-(2-(S)-Guanidino-6-guanidino-hexanoyl)-piperazin-1-yl]-1,1-dimethyl-2-oxo-ethyl]-2,4-dichloro-3-(2-methyl-quinolin-8-yloxy-methyl)-benzenesulfonamidetris trifluoroacetate;(R)—N-[4-(3-(S)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxy-methyl)-benzenesulfonamidetris trifluoroacetate;(R)—N-{2-[4-(4-2(Guanidino)ethyl]piperazin-1ylacetyl)-piperazin-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetetra trifluoroacetate;(R)—N-[4-(3-(S)-Amino-6-amino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;(R)—N-[4-(3-(S)-Guanidino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;(R)—N-[4-(3-(S)-Amino-6-dimethylamino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;(S)—N-[4-(2-(S)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxy-methyl)-benzenesulfonamidetris trifluoroacetate;(S)—N-[4-(3-(S)-Amino-6-guanidino-hexanoyl)-piperazine-1-carbonyl]-1-methyl-propyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxy-methyl)-benzenesulfonamidetris trifluoroacetate;2,4-Dichloro-N-{1-[4-(3(S),6-diamino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl}-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;2,4-Dichloro-N-{1-[4-(3(S),6-diguanidino-hexanoyl)-piperazine-1-carbonyl]-cyclopentyl}-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-(1-{4-[3-(S),6-Bis-(N′,N″-dicyclohexyl-guanidino)-hexanoyl]-piperazine-1-carbonyl}-cyclopentyl)-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzensulfonamidetris trifluoroacetate;N-{1-[4-(2-(S)Amino-3-piperidin-4-yl-propionyl)-piperazine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-{1-[4-(2-Trimethylammonium-acetyl)-piperazine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidebis trifluoroacetate;N-{1-[4-(4-Trimethylammonium-butanoyl)-piperazine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidebis trifluoroacetate;N-{1-[4-(3(R)-Hydroxy-4-trimethylammonium-butanoyl)-piperazine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxy-methyl)-benzenesulfonamidebis trifluoroacetate;N-[1-[4-(2-(S)-Dimethylamino-6-dimethylamino-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxy-methyl)-benzenesulfonamidetris trifluoroacetate;{5-[(1-{1-[2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzensulfonylamino]-cyclopentanecarbonyl}-piperidin-4-ylmethyl)-dimethyl-ammonium]pentyl}-trimethyl-ammoniumtris trifluoroacetate;{5-[(1-{1-[2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzensulfonylamino]-cyclopentanecarbonyl}-piperidine-4-carbonyl)-amino]-pentyl}-trimethyl-ammoniumbis trifluoroacetate;N-[1-[4-(2-(S)-Trimethylammonium-6-trimethylammonium-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-[1-[4-(2-(R)-Trimethylammonium-6-trimethylammonium-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-[1-[4-(2-(S)-Trimethylammonium-6-amino-hexanoyl)-piperazin-1-yl]-cyclopentyl]-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-{1-[4-(6-Trimethylammonium-hexanoyl)-piperazine-1-carbonyl]-cyclopentyll}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidebis trifluoroacetate;N-(6-Amino-hexyl)-4-{2-[2,4-dichloro-3-(2-methyl-quinolin-8-yloxy-methyl)-benzenesulfonylamino]-2-methyl-propionyl}-piperazine-1-carboxamidine;N-[2-(3-Amino-propylamino)-ethyl]-4-{2-[2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-2-methyl-propionyl}-piperazine-1-carboxamidine;N-(3-Amino-propyl)-4-{2-[2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-2-methyl-propionyl}-piperazine-1-carboxamidinebis trifluoroacetate;N-(6-Amino-hexyl)-4-{1-[2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclopentanecarbonyl}-piperazine-1-carboxamidinebis trifluoroacetate;N-[2-(3-Amino-propylamino)-ethyl]-4-{1-[2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclo-pentanecarbonyl}-piperazine-1-carboxamidinebis trifluoroacetate:N-[2-(4-{1-[2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclopentanecarbonyl}-piperazin-1-yl)-ethyl]-4-methyl-piperazine-1-carboxamidinebis trifluoroacetate;2,4-Dichloro-N-{1-(4-(2(R),6-diamino-hexyl)-piperazine-1-carbonyl]-cyclopentyl}-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzene-sulfonamidetetra trifluoroacetate;2,4-Dichloro-N-{1-[4-(2(R),6-diguanidino-hexyl)-piperazine-1-carbonyl]-cyclopentyl}-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetetrahydrochloride2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-N-{1-[4-(2-piperazin-1-yl-ethyl)-piperazine-1-carbonyl]-cyclopentyl}-benzenesulfonamidetetra trifluoroacetate;2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-N-{1-[4-(2-piperidin-4-yl-ethyl)-piperazine-1-carbonyl]-cyclopentyl}-benzene-sulfonamide;{3-[(4-{1-[2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclopentanecarbonyl}-piperazine-1-carboximi-doyl)-amino]propyl}-trimethyl-ammoniumtris trifluoroacetate;4-{1-[2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzene-sulfonylamino]-cyclopentanecarbonyl}-N-(3-dimethylamino-propyl)-piperazine-1-carboxamidinetris trifluoroacetate;N-(1-{4-[(5-Amino-pentylamino)-methyl]-piperidine-1-carbonyl}-cyclopentyl)-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;N-{1-[4-(4-Amino-piperidin-1-ylmethyl)-piperidine-1-carbonyl]-cyclopentyl}-2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonamidetris trifluoroacetate;2,4-Dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-N-(1-{4-[(5-methylamino-pentylamino)-methyl]-piperidine-1-carbonyl}-cyclopentyl)-benzenesulfonamidetris trifluoroacetate;Amino-6-(4-{1-[2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]-cyclopentanecarbonyl}-piperazin-1-yl)-6-oxo-hexyl]-trimethyl-ammoniumbis trifluoroacetate.
 8. Intermediates of general formula (6) or (7)

in which R₁ can be H or methyl, R₂ and R₃ can be independently methyl,ethyl or, together with the carbon atom which they are linked to, form acyclopentyl group, and R₁₄ is methyl or t-butyl.
 9. Intermediates ofgeneral formula (1)

in which R₁ can be H or methyl, R₂ and R₃ can be independently methyl,ethyl or, together with the carbon atom which they are linked to, form acyclopentyl group.
 10. Pharmaceutical compositions containing as activeingredient a compound as claimed in claim 1, together withpharmaceutically acceptable excipients, for the treatment of disordersin which the use of a bradykinin antagonist is needed.
 11. The use of acompound as claimed in claim 1, for the preparation of pharmaceuticalcompositions for the treatment of disorders in which the use of abradykinin antagonist is needed.
 12. The use of a compound as claimed inclaim 11 for the preparation of pharmaceutical compositions for thetreatment of inflammatory, allergic and autoimmune disorders.
 13. Theuse of a compound as claimed in claim 11 for the preparation ofpharmaceutical compositions for the treatment of disorders such asasthma and chronic bronchitis, allergic, vasomotor and viral rhinitis,obstructive pulmonary disease (COPD), rheumatoid arthritis, chronicinflammatory diseases of the bowel (Crohn's disease and ulcerativecolitis), glomerulonephritis, psoriasis, rash, acute and chroniccystitis, hepatic cirrhosis, glomerulopathies and pulmonary fibrosis,arteriosclerosis, both acute and chronic pain, septic, allergic andpost-traumatic shocks, hepatic cirrhosis by hepatorenal syndrome,hypotension, alopecia, or as anticancer and antiangiogenetics.